Clinical trial NCT04402008
Conditions: NSCLC
Keywords: EGFR HER2 Exon 20 insertion mutation
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2020-06-23; Completion date: 2023-02-15
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 1/2, open-label, multicenter study to determine dose, tolerability, safety and efficacy of poziotinib in Japanese patients non-small cell lung cancer (NSCLC).

Detailed description:
This is a Phase 1/2, open-label, multicenter study in Japanese patients with locally advanced or metastatic NSCLC. This study will be conducted in two parts. Phase 1 is designed to observe the maximum tolerated dose (MTD) or maximum administered dose (MAD) of poziotinib when administered once daily or twice daily. Phase 2 will evaluate the safety and efficacy of the dose determined in Phase 1. Study participation includes a 30 day screening period, up to 24 months of treatment, and long-term follow-up for a maximum of 24 months after discontinuation of study treatment.

Phase 1 will enroll up to 36 patients into a dose finding study with two parallel, randomized dose groups. Each group will undergo a dose-finding scheme using a 3+3 design with the assessment of dose-limiting toxicities (DLTs) at up to three dose levels. Patients will be randomized into once daily (QD) or twice daily (BID) dose groups. The DLT assessment will be conducted in the first cycle of treatment and therefore, poziotinib dose modifications are not permitted during this cycle. Patients will be hospitalized for the first 2 weeks.

Phase 2 will enroll 40 additional NSCLC patients with epidermal growth factor receptor (EGFR) (20 patients) or human epidermal growth factor 2 (HER2) (20 patients) exon 20 insertion mutations. Efficacy and safety of the dose and dosing regimen determined in Phase 1 will be evaluated. All patients will be treated in 28-day cycles for up to 24 months.

Arms: arm 1: Dose finding at 8 mg, 12 mg, or 16 mg of poziotinib once daily in 28-day treatment cycles. arm 2: Dose finding at 4 mg, 6 mg, or 8 mg of poziotinib twice daily in 28-day treatment cycles. arm 3: Once Daily or Twice Daily Dosing as determined in Phase 1 in 28-day treatment cycles.

Cohort 1: EGFR exon 20 insertion mutations

Cohort 2: HER2 exon 20 insertion mutations
Interventions: intervention 1: Poziotinib Once Daily Dosing intervention 2: Poziotinib Twice Daily Dosing intervention 3: Poziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1
Intervention descriptions: intervention 1: The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration. intervention 2: The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration. intervention 3: The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Phase 1/2 Dose Finding Study of Poziotinib in Japanese Patients 
With Locally Advanced or Metastatic Non-Small Cell Lung Cancer 
(NSCLC) 
NCT Number: NCT04402008 
Document Date: Protocol Amendment 2: 04 March 2020 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
1 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Study Title:  
A Phase 1/2 Dose Finding Study of Poziotinib in Japanese 
Patients with Locally Advanced or Metastatic Non-Small Cell 
Lung Cancer (NSCLC)  
Study Number:  
SPI-POZ-104 
Study Phase:  
Phase 1/2  
Study Drug:  
Poziotinib 
IND Number:  
135,719 
Sponsor:  
Spectrum Pharmaceuticals, Inc. 
Research and Development Office  
157 Technology Drive 
Irvine, CA 92618 
USA 
In-Country Caretaker 
for Clinical trial (ICCC) 
IQVIA Services Japan K.K. 
4-10-18 Takanawa, Minato-ku,  
Tokyo, 108-0074, Japan 
Protocol Version/Date:  
Amendment 2/04 Mar 2020 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312, ICH guidelines, MHLW Article 14, Paragraph 3 and Article 80-2 of the “Law on Securing Quality, 
Efficacy and Safety of Products including Pharmaceuticals and Medical Devices”, and MHLW “Ministerial 
Ordinance on GCP for Drugs”), applicable government regulations and applicable 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 this protocol. You will not disclose any of the information to others without prior written authorization 
from Spectrum Pharmaceuticals, Inc. except to the extent necessary to obtain Informed Consent from those persons 
to whom the investigational drug may be administered. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
2 
INVESTIGATOR SIGNATURE 
Protocol Number: SPI-POZ-104 
A Phase 1/2 Dose Finding Study of Poziotinib in Japanese Patients with Locally Advanced 
or Metastatic Non-Small Cell Lung Cancer (NSCLC)  
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 drug, 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 conduct of this 
study. I will discuss this material with them to assure that they are fully informed regarding the 
investigational drug and the conduct of the study. 
I will perform the study according to the specifications outlined in this 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 from the IRB/EC 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 this study will be released without prior 
written consent from Spectrum Pharmaceuticals, Inc., unless this requirement is superseded by 
the applicable territory’s regulatory authority (e.g., PMDA). 
__________________________________ 
Principal Investigator Name (PLEASE PRINT): 
Signature: ________________________________ Date ______________ 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
3 
SYNOPSIS  
Title of Study: A Phase 1/2 Dose Finding Study of Poziotinib in Japanese Patients with Locally Advanced 
or Metastatic Non-Small Cell Lung Cancer (NSCLC)  
Name of Sponsor: Spectrum Pharmaceuticals, Inc. 
Name of Investigational Product: Poziotinib 
Study Centers: Approximately 20 study centers in Japan  
Duration of Study: Approximately 3 years 
Planned Number of Patients:  
Phase 1 – Dose-Finding: Approximately 36 patients 
Phase 2 - Efficacy: 40 patients (20 patients per cohort) 
Clinical Phase: 1/2 
Objectives:  
To evaluate the following in NSCLC patients treated with poziotinib:  
Primary Objective 
• 
Phase 1: Dose-Finding - Maximum Tolerated Dose (MTD) or Maximum Administered Dose 
(MAD)  
• 
Phase 2: Efficacy - Objective Response Rate (ORR)  
Secondary Objectives 
• 
Phase 1: Dose-Finding 
• 
Pharmacokinetics of poziotinib and M1 and M2 metabolites 
• 
Safety and Tolerability 
• 
Phase 2: Efficacy 
• 
Disease Control Rate (DCR) 
• 
Duration of Response (DoR) 
• 
Progression-Free Survival (PFS)  
• 
Pharmacokinetics of poziotinib and M1 and M2 metabolites 
• 
Safety and Tolerability  
Exploratory Objective 
• 
Overall Survival 
Duration of Study: 
It is estimated that the first patient will be enrolled in June 2020 and the last patient visit will occur 
approximately March 2025. The duration of study participation for each patient, in general, includes the 
following segments:  
• 
Screening Period: up to 30 days 
• 
Treatment Period: 28 days per cycle for up to 24 months of treatment or until disease progression, 
death, intolerable adverse events (AEs), or other protocol-specified reason for patient withdrawal  
• 
Safety Follow-up Visit: 35 (±5) days after the last dose of poziotinib  
• 
Long-Term Follow-up: After study drug discontinuation, patients who have consented will be 
contacted every 3 months, for up to 2 years after patient’s first dose of poziotinib, for survival 
assessment 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
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Study Design and Treatment Plan: 
This is a Phase 1/2, open-label, multicenter dose finding study to determine the MTD/MAD of poziotinib when 
administered once daily (QD) or twice daily (BID) to Japanese participants with locally advanced or metastatic 
NSCLC.  
Phase 1: Dose-Finding and Safety 
Phase 1 is a dose finding study with two parallel, randomized dose groups. Each group will undergo dose-
finding scheme using a 3+3 design with the assessment of dose-limiting toxicities (DLTs) at up to three dose 
levels. Patients will be hospitalized for the first 2 weeks of Cycle 1.  
• 
Group 1 (once daily dosing [QD]): Starting dose of 8 mg. 
• 
Group 2 (twice daily dosing [BID]): Starting dose of 4 mg BID. 
The DLT assessment will be conducted in Cycle 1 of the Phase 1 of the study. Poziotinib dose-finding will 
proceed based on the occurrence of DLTs during Cycle 1. Although DLTs will be evaluated based on the list of 
criteria specified below, toxicity related to the onset of any unexpected adverse events will be evaluated as well 
in addition to the DLTs. The MTD or MAD will be determined in each group independently. The DLTs for 
MTD/MAD will be assessed by the Medical Monitor in consultation with the site Principal Investigator. In 
addition to the defined DLTs, dose advancement/MTD will be decided based on all safety information, including 
adverse events that the subject experiences that are not defined as DLTs. A DLT will be any of the following 
treatment-related adverse events that occur during Cycle 1, despite optimal medical supportive therapy: 
Non-Hematological Toxicity:  
• 
Grade 3 or higher toxicity based on NCI-CTCAE (version 5.0), except for alopecia 
• 
Grade 3 or higher nausea and vomiting, despite treatment with oral anti-emetics at the highest dose 
• 
Grade 3 or higher diarrhea, despite diarrhea treatment at the highest dose 
Hematological Toxicity: 
• 
Grade 4 or higher neutropenia (ANC<0.5×109/L) sustained for 7 days or more 
• 
Febrile neutropenia (ANC<1.0×109/L with a single temperature of >38.3°C (101°F) or a sustained 
temperature of ≥38°C (100.4°F) for more than one hour) 
• 
Neutropenic infection: Grade 3 or higher infection accompanying Grade 4 neutropenia 
(ANC<0.5×109/L) (requiring IV antibiotic, antifungal or antiviral agent administration/ requiring 
radiation or surgical therapy) 
• 
Grade 4 thrombocytopenia (PLT<25,000/mm3) or any grade thrombocytopenia requiring platelet 
transfusion 
However, in case of ANC<0.5×109/L, conduct a repeat test on at least the 7th day in order to verify if it is lasted 
for 7 days or more. 
Because Phase 1 is for DLT assessment and dose finding, poziotinib dose modifications are not permitted during 
Cycle 1 in Phase 1. Dose modifications are permitted beginning with Cycle 2 based on Sponsor 
recommendations.  
Phase 2: Efficacy 
Once the MTD/MAD is determined, 40 additional NSCLC patients with EGFR (20 patients) or HER2 
(20 patients) exon 20 insertion mutations (including duplication mutations) will be enrolled to evaluate the 
efficacy of poziotinib at the dose and dosing regimen determined in Phase 1. The choice of QD or BID for Phase 
2 will be determined by the sponsor and the treatment regimen is selected by the Sponsor, Dose modifications 
are permitted based on Sponsor recommendations and notification of the Medical Monitor.  
During each 28-day cycle, patients who are eligible for participation will receive poziotinib at the assigned dose, 
orally, QD or BID, depending on the dose identified in Phase 1, continuously. All patients will be treated for up 
to 24 months or until disease progression, death, intolerable adverse events (AEs), other protocol-specified 
reasons for patient withdrawal. 


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Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
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Patient Replacement Strategy: Patients in Phase 1 who discontinue from the study before completing Cycle 1 
treatment for reasons other than DLTs will be replaced.  
Inclusion & Exclusion Criteria:  
Inclusion Criteria: 
1. Patient is at least 20 years of age  
2. Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit 
schedules, and meeting all study requirements  
3. Phase 2: If an archival tissue sample is not available, a tumor biopsy will be required.  
4. Previously treated patient with histologically or cytologically confirmed (archival tissue accepted) 
locally advanced or metastatic non-small cell lung cancer (NSCLC) and is not a candidate for definitive 
therapy  
• 
Phase 1: No test for mutational status is required  
• 
Phase 2: Documented EGFR or HER2 exon 20 insertion mutation (including duplication mutations) 
in NSCLC patients. Patients will be enrolled based on documentation of mutational status using 
PCR or a validated next generation sequencing detection analysis test.  
• 
Documented EGFR exon 20 insertion mutation, including D770_N771insSVD, 
D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other EGFR exon 20 in-
frame insertion mutation (including duplications).  
• 
Documented HER2 exon 20 insertion mutation, including A775_G776insYVMA, 
G776_V777insVC, or P780_Y781insGSP, or any other HER2 exon 20 in-frame insertion 
mutation (including duplications).  
5. Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid Tumors 
(RECIST, version 1.1). Metastatic lesions in bone, CNS, or in brain cannot be used for target lesions.  
6. Prior treatment status: 
• 
Phase 1: Patient with refractory NSCLC to available standard therapies  
• 
Phase 2: Progression after at least one systemic therapy for locally advanced or metastatic disease 
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1  
8. Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for non-
hematologic toxicities (except for Grade ≤2 peripheral neuropathy) and has adequate hematologic, 
hepatic, and renal function at Baseline, as defined by: 
• 
Leukocytes ≥3.0×109/L 
• 
Absolute neutrophil count (ANC) must be ≥1.5×109/L  
• 
Platelet count ≥100×109/L 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤2 mg/dL; if hepatic metastases are present, ≤2.5×ULN  
• 
SGOT (AST) and SGPT (ALT) ≤2.5×ULN with the following exception; Patients with liver 
metastases AST, ALT ≤5×ULN  
9. Patient is willing to practice 2 forms of contraception, one of which must be a barrier method. Female 
patients of childbearing potential must use an effective method of birth control (e.g., oral contraceptive, 
intrauterine device, bilateral tubal ligation/occlusion, condoms, diaphragm, not engaging in sexual 
intercourse) during treatment period and 3 months thereafter. Males must use an effective method of 
birth control (e.g., condoms, vasectomy, or not engaging in sexual intercourse) during treatment period 
and 3 months thereafter.   
10. Females of childbearing potential must have a negative pregnancy test within 7 days prior to Cycle 1, 
Day 1. Females who are postmenopausal for at least 1 year (defined as more than 12 months since last 
menses) with no other medical reasons or who are surgically sterilized do not require this test.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
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Exclusion Criteria: 
1. Phase 2: Patient has EGFR T790M mutation or any other acquired EGFR exon 20 point mutation  
2. Phase 2 Only: Patient has had previous treatment with poziotinib. The currently approved TKIs that are 
not considered to be exon 20 insertion-selective are permissible.  
3. Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; 
systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks prior to 
Cycle 1, Day 1; local radiation therapy for bone pain may be allowed.  
4. Patient has used strong inhibitors/inducers of CYP3A4 and CYP2D6 within 1 month prior to Cycle 1, 
Day 1.  
5. Patient has brain metastases and is clinically symptomatic, requires high dose or increasing doses of 
systemic corticosteroids, or needs any anticonvulsant therapy for metastatic brain disease.  
6. Patient has a high risk for or 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. Cardiac ejection fraction <50% as determined by either echocardiogram (ECHO) or multi-
gated acquisition (MUGA) during Screening.  
7. Patient has had another primary malignancy within 3 years prior to starting study treatment, except for 
adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ  
8. 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 5.0) Grade 2 or above diarrhea due to other 
etiologies  
9. Patient has an active Grade ≥2 skin disorder, rash, mucositis, or skin infection that needs medication or 
therapy or existing Grade ≥2 skin toxicity from previous therapies; Grade >2 neuropathy, Grade ≥2 
pneumonitis.  
10. 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  
11. 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). Patient has active HBV or HCV 
infection. 
12.  Patient is HIV antibody positive. 
13. Patient currently has or has had interstitial lung disease in the past. 
14. Patient has known hypersensitivity to poziotinib or has a history of allergic reactions attributed to 
chemically similar compounds or other tyrosine kinase inhibitors (TKIs)  
15. Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that 
would not be appropriate for this study  
16. Patient has unstable, uncontrolled, active bleeding disorders that the investigator considers that the 
patient could be at increased risk or not be suitable for treatment in this study  
17. Patient is pregnant.  
18. Women who are breastfeeding or women who are not willing to stop breastfeeding during study 
treatment period and for 30 days after the last dose of study drug. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
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Investigational Product, Dose, and Route of Administration:  
Poziotinib is supplied as 8-mg tablets and 2-mg tablets. Poziotinib should be taken orally with food and a glass 
of water (approximately 240 mL) at approximately the same time(s) each day.  
Once a Day Dosing:  
• 
Phase 1, Days 1 to 14: Patients will be administered poziotinib every 24 (±1) hours. 
• 
Phase 1 post-Hospitalization and Phase 2: If the daily dose is missed, this dose may be administered 
any time during the day, but at least 8 hours prior to the next scheduled dose. 
Twice a Day Dosing:  
• 
Phase 1, Days 1 to 14: Patients will be administered poziotinib every 12 hours (±30 minutes) 
• 
Phase 1 post-Hospitalization and Phase 2: The first dose should be taken in the morning and the 
second dose should be taken approximately 8 to 12 hours later. If a dose is missed, and there is less than 
8 hours before the next scheduled dose, the dose should be skipped and the next dose taken as scheduled. 
Reference Therapy, Dose, and Route of Administration: None  
Efficacy Assessments: 
Clinical staging will be performed at Baseline, with follow-up at 4 weeks, 8 weeks, and every 8 weeks 
thereafter. Efficacy will be based on the radiologic assessment by the site’s Principal Investigator using 
RECIST 1.1 criteria.  
Primary Endpoint: 
• 
Phase 1: Dose-Finding: MTD or MAD 
• 
Phase 2: Efficacy: Objective Response Rate (ORR, complete response+partial response) 
Secondary Endpoints: 
• 
Phase 1: Dose-Finding 
• 
Pharmacokinetics of poziotinib and M1 and M2 metabolites 
• 
Safety and Tolerability 
• 
Phase 2: Efficacy 
• 
Disease Control Rate (DCR, complete response+partial response+stable disease) 
• 
Duration of Response (DoR) 
• 
Progression-Free Survival (PFS)  
• 
Safety and Tolerability 
Exploratory Endpoint:  
• 
Overall Survival 
Pharmacokinetic Assessments: The pharmacokinetics of poziotinib and the M1 and M2 metabolites will be 
characterized. 
Phase 1 - Dose-Finding and Safety: On Cycle 1, Day 1 and Cycle 1, Day 13, all patients will have intensive 
PK blood samples drawn predose and 30 minutes, 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose. In addition, if a 
patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, pneumonitis), 
PK blood samples will be collected as soon as possible following the onset of the AE and the time of the last 
dose and the time of blood draw should be recorded .  
Phase 2 - Efficacy: All patients will have blood samples drawn predose and at 1 hour and 2 hours postdose on 
Cycle 1, Day 1 and Cycle 2, Day 1 for sparse PK sampling and time-matched concentration-ECG analysis. 
Blood samples will also be collected at each imaging session in order to correlate poziotinib concentrations with 
circulating tumor DNA (ctDNA) and efficacy; the time of the last dose and the time of blood draw should be 
recorded.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
8 
In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, 
pneumonitis), a blood sample will be collected as soon as possible following the onset of the AE, and the time of 
the last dose and the time of blood draw should be recorded. 
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. The grade of TEAEs will be assessed based on CTCAE, version 5.0.  
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, all serious adverse events (SAEs) will be reported. In addition, SAEs that occur after 35 (±5) 
days after the last dose of study treatment where a causal relationship with the study drug is suspected will also 
be recorded. 
Statistical Methods: 
Sample Size Justification: 
The total sample size for this study is approximately 76 patients. Phase 1 is a dose finding study using “3+3” 
design to determine the MTD/MAD in each dosing group (QD or BID). Up to 18 patients (up to 3 dose levels, 
up to 6 patients each level) will be included for DLT evaluation in each dosing group for a total of 36 patients in 
Phase 1. Patients who discontinue from the study before completing Cycle 1 treatment for reasons other than 
DLTs are not qualified for DLT evaluation and will be replaced. 
A total of 40 patients (20 patients each in EGFR and HER2 mutation cohorts) will be enrolled in the dose 
confirmatory group in Phase 2 to confirm the activity in the identified poziotinib dose and schedule. The sample 
size of 20 patients in each mutation cohort in Phase 2 will provide a width for 95% confidence interval of 0.424 
for the expected ORR of 30%.  
Efficacy Analysis:  
The primary efficacy variable ORR will be analyzed descriptively along with the 95% CI for each cohort. The 
determination of the ORR will be based upon radiographic assessment by the site’s Principal Investigator using 
RECIST Version 1.1. The secondary outcomes, DCR, DoR, and PFS, will be analyzed using descriptive 
statistics, for each cohort, and with 95% CI for DCR and Kaplan-Meier plot for DoR and PFS.  
Analysis Populations: 
The following analysis populations have been defined for each cohort: 
• 
The Evaluable Population consists of all patients in Phase 2 who are enrolled, complete at least 1 cycle 
of poziotinib treatment, and are evaluable for tumor response based on RECIST, Version 1.1 criteria. 
The efficacy data will be analyzed using the Evaluable Population.  
• 
The Safety Analysis Population 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 Safety Analysis 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 the grading by CTCAE, Version 5.0.  
Protocol Version/Date: Amendment 2/04 Mar 2020 










Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
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r) 
On Cycle 1, Day 1 and Cycle 1, Day 13, patients will have intensive pharmacokinetic (PK) samples drawn (4 mL whole blood at each time point) predose and 30 minutes, 1 and 2 (±15 minutes) 
postdose, and 3, 4, 6, 8, 12, 14 (±30 minutes) postdose, and 24 hours (±1 hour) postdose. In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, 
diarrhea, pneumonitis), blood samples will be collected as soon as possible following the onset of the AE and the time of the last dose and the time of blood draw should be recorded  
s) 
Poziotinib will be dispensed on Day 1 of each cycle. Poziotinib should be taken with food and a glass of water (approximately 240 mL) at approximately the same time(s) each day.  
t) 
During the Screening Period, only SAEs  will be recorded . All AEs will be collected from Cycle 1, Day 1 through the Safety Follow-up Visit. Patients will be hospitalized during the first 2 weeks of 
the study and will be monitored for safety assessments including AEs, vital signs, ECGs on Day 7 and Day 14 of Cycle 1. Adverse events will be assessed daily while hospitalized. 
u) 
Telephone contact for AE and concomitant medication assessment on Cycle 1, Day 22 (±2 days), weekly during Cycle 2 and then Day 15 (±2 days) in subsequent cycles. During the long-term follow-
up patients will be contacted every 3 months to assess survival.  






Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
Confidential 
16 
s) 
Cardiac ejection fraction will be evaluated using echocardiogram or multi-gated acquisition (MUGA) scan at Screening. The Investigator can order subsequent tests based on patient standard of care.  
t) 
Patients will have blood samples drawn predose and at 1 hour and 2 hours (±15 min) postdose on Cycle 1, Day 1 and Cycle 2, Day 1 for sparse PK sampling and time-matched concentration-ECG 
analysis. Blood samples will be collected at Cycle 3 Day 1 and then every 8 weeks in order correlate poziotinib concentrations with plasma ctDNA and efficacy; the time of the last dose and the time 
of blood draw should be recorded. In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, pneumonitis), blood samples will be collected as 
soon as possible following the onset of the AE and the time of the last dose and the time of blood draw should be recorded.  
u) 
Poziotinib will be dispensed on Day 1 of each cycle. Poziotinib should be taken with food and a glass of water (approximately 240 mL) at approximately the same time(s) each day.  
v) 
During the Screening Period, only SAEs  will be recorded . All AEs will be collected from Cycle 1, Day 1 through the Safety Follow-up Visit.  
w) Concomitant medications will be collected at Day 1 of each cycle, Day 8 and Day 15 during Cycle 1, and at the Safety Follow-up Visit. 
x) 
Telephone contact will be made to collect AE and concomitant medication information from patients on Cycle 1, Day 22, every week in Cycle 2, and Day 15 (±2 days) in each cycle thereafter. 
During the long-term follow-up patients will be contacted every 3 months to assess survival.  
 
 




Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
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in the opinion of the Principal Investigator the patient has developed signs or symptoms of Grade 
≥2 pneumonitis (CTCAE Version 5.0), the patient would stop dosing and depending on the 
response/recovery may be discontinued from the study. If the patient has developed signs or 
symptoms of Grade 1 pneumonitis, the Investigator can stop treatment after 
consultation/discussion with the Medical Monitor. 


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Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-104 
Amendment 2/04 Mar 2020 
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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
INVESTIGATOR SIGNATURE ..................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................19 
List of Tables ..........................................................................................................................21 
List of Figures .........................................................................................................................21 
1 
INTRODUCTION ................................................................................................................23 
1.1 
Background ................................................................................................................23 
1.1.1 
Human Epidermal Growth Factor Receptor Family and Cancer ................23 
1.1.2 
Poziotinib ............................................................................................................24 
1.1.3 
Poziotinib Clinical Studies ................................................................................32 
1.2 
Rationale for the Current Study ...............................................................................36 
2 
STUDY OBJECTIVES ........................................................................................................38 
2.1 
Primary Objective ......................................................................................................38 
2.2 
Secondary Objectives.................................................................................................38 
2.3 
Exploratory Objective ...............................................................................................38 
3 
INVESTIGATIONAL PLAN ..............................................................................................39 
3.1 
Study Design and Treatment Plan............................................................................39 
3.1.1 
Phase 1: Dose-Finding .......................................................................................39 
3.1.2 
Phase 2: Efficacy ................................................................................................40 
3.2 
Study Duration ...........................................................................................................43 
4 
PATIENT POPULATION ...................................................................................................43 
4.1 
Inclusion Criteria .......................................................................................................43 
4.2 
Exclusion Criteria ......................................................................................................44 
4.3 
Patient Discontinuation/Withdrawal Criteria .........................................................45 
5 
STUDY PROCEDURES ......................................................................................................46 
5.1 
Screening .....................................................................................................................46 
5.2 
Patient Assignment ....................................................................................................46 
5.3 
Timing of Assessments and Procedures ...................................................................47 
5.3.1 
Screening Visit ...................................................................................................47 
5.3.2 
Treatment Period – Cycle 1, Day 1 ..................................................................48 
5.3.3 
Phase 1, Cycle 1, Days 2-14, in the Hospital ....................................................48 
5.3.4 
Criteria for Discharge After Day 14 During DLT Evaluation Period (Phase 
1 only) ...............................................................................................................49 
5.3.5 
Phase 2, Cycle 1, Day 8 and 15 (±2 days) (Phase 2 Only) ..............................50 
5.3.6 
Treatment Period - Telephone Contact (Both Phases) ..................................50 
5.3.7 
Treatment Period Office Visit – Cycle 2+, Day 1 ...........................................50 
5.3.8 
Safety Follow-up/End-of-Study Visit (35 [±5] Days after Last Dose of Study 
Treatment) .......................................................................................................51 


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5.3.9 
Long-Term Follow-up – Every 3 Months ........................................................51 
5.4 
Description of Study Assessment Parameters .........................................................52 
5.4.1 
Relevant Medical History .................................................................................52 
5.4.2 
Physical Examination ........................................................................................52 
5.4.3 
Vital Signs ...........................................................................................................52 
5.4.4 
Pulmonary Function and Resting Oxygen Saturation ...................................52 
5.4.5 
ECOG Performance Status ..............................................................................53 
5.4.6 
Tumor Assessment .............................................................................................53 
5.4.7 
Tissue, Plasma, and Whole Blood Samples .....................................................53 
5.4.8 
Pharmacokinetics ..............................................................................................54 
5.4.9 
Clinical Laboratory Tests .................................................................................55 
5.4.10 
Hepatitis B, Hepatitis C, and HIV Tests ..........................................................55 
5.4.11 
Electrocardiogram .............................................................................................56 
5.4.12 
Cardiac Ejection Fraction ................................................................................56 
5.4.13 
Concomitant Medications .................................................................................56 
5.4.14 
Patient Discharge ...............................................................................................58 
6 
STUDY DRUG AND PHARMACEUTICAL INFORMATION .....................................58 
6.1 
Poziotinib ....................................................................................................................58 
6.2 
Poziotinib Composition .............................................................................................58 
6.3 
Poziotinib Supply and Labeling ................................................................................58 
6.4 
Poziotinib Storage and Handling ..............................................................................58 
6.5 
Poziotinib Administration .........................................................................................59 
6.6 
Diarrhea Management...............................................................................................59 
6.7 
Poziotinib Dose Modification Recommendations ...................................................59 
7 
SAFETY ASSESSMENT .....................................................................................................61 
7.1 
Safety Measures .........................................................................................................61 
7.2 
Adverse Events ...........................................................................................................61 
7.3 
Guidelines for Recording and Attribution Scoring of Adverse Events ................62 
7.3.1 
Recording of Adverse Events ...........................................................................62 
7.3.2 
Grading of Adverse Events ...............................................................................63 
7.4 
Follow-up of Adverse Events ....................................................................................63 
7.5 
Relationship ................................................................................................................63 
7.6 
Expectedness ...............................................................................................................63 
7.7 
Serious Adverse Events .............................................................................................64 
7.7.1 
Serious Adverse Event Reporting ....................................................................64 
7.7.2 
Exclusions to Serious Adverse Event Reporting Requirements ....................65 
7.8 
Reproductive Risks ....................................................................................................65 
8 
STATISTICAL PLAN..........................................................................................................66 
8.1 
Sample Size .................................................................................................................66 
8.2 
Method of Treatment Assignment ............................................................................66 
8.3 
Analysis Populations ..................................................................................................67 
8.4 
General Statistical Methods ......................................................................................67 
8.5 
Efficacy Analyses .......................................................................................................67 
8.5.1 
Secondary Endpoints .........................................................................................67 


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8.5.2 
Exploratory Endpoints ......................................................................................68 
8.6 
Safety Analysis ...........................................................................................................68 
8.6.1 
Safety and Adverse Events ...............................................................................68 
8.6.2 
Pharmacokinetics ..............................................................................................68 
9 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT ........................69 
9.1 
Investigator and Study Site Responsibilities ...........................................................69 
9.1.1 
Good Clinical Practice ......................................................................................69 
9.1.2 
Institutional Review Board/Ethics Committee Approval ..............................69 
9.1.3 
Informed Consent ..............................................................................................69 
9.1.4 
Study Files and Retention of Records ..............................................................70 
9.2 
Recording and Collecting of Data ............................................................................70 
9.2.1 
Case Report Forms ............................................................................................70 
9.2.2 
Drug Accountability ..........................................................................................70 
9.3 
Protocol Compliance ..................................................................................................71 
9.4 
Sponsor Responsibilities ............................................................................................71 
9.4.1 
Safety Monitoring ..............................................................................................71 
9.5 
Joint Investigator/Sponsor Responsibilities ............................................................71 
9.5.1 
Access to Information for Monitoring and Auditing .....................................71 
9.5.2 
Termination of the Study ..................................................................................71 
9.6 
Confidentiality ............................................................................................................72 
10 REFERENCES .....................................................................................................................73 
 
PHASE 1 SCHEDULE OF ASSESSMENTS AND PROCEDURES .........75 
 
PHASE 2 SCHEDULE OF ASSESSMENTS AND PROCEDURES .........78 
 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE ..................................................................................................................81 
 
RASH MANAGEMENT RECOMMENDATIONS ....................................82 
 
List of Tables 
Table 1 
Most Common Treatment-Emergent Adverse Events (≥10% in Group Total for 
each Study) in patients receiving 12 mg Per Day and 16 mg Per Day Poziotinib 
in Completed Phase 1 and Phase 2 Studies ............................................................35 
Table 2 
Examples of Important Clinical Inhibitors/Inducers/Substrates for P450 
Enzymes Involved in the Metabolism of Poziotinib...............................................57 
Table 3 
Recommendations for Dose Reductions after Cycle 1 in Phase 1 and During 
Phase 2 .......................................................................................................................60 
Table 4 
Investigator Assessment of Adverse Event Causality ............................................63 
 
List of Figures 
Figure 1 
IL-3-Independent Survival of Ba/F3 Cells Stably Expressing EGFR Exon 20 
Mutations ...................................................................................................................25 


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Figure 2 
Poziotinib (HM781-36B) is a Potent Inhibitor of Cell Lines with EGFR Exon 20 
Insertions ...................................................................................................................26 
Figure 3 
Effect of Poziotinib (HM781-36B) on EGFR Phosphorylation and Downstream 
Signaling ....................................................................................................................26 
Figure 4 
Tumor Volume Change in Mice with EGFR Exon 20 Insertion Mutations 
Treated with Poziotinib Vs Vehicle .........................................................................27 
Figure 5 
a) Ba/F3 Cells Expressing HER2 Mutations are Sensitive to Poziotinib 
b) Poziotinib Inhibits HER2 Phosphorylation .......................................................28 
Figure 6 
Tumor Volume Change in Mice with HER2 Exon 20 Insertion Mutations - 
Treated with Poziotinib vs Vehicle ..........................................................................28 
Figure 7 
Poziotinib Inhibits Growth of Atypical EGFR Mutant Ba/F3 Cell Lines ...........29 
Figure 8 
Poziotinib Inhibits Growth of Atypical HER2 Mutant Ba/F3 Cell Lines............30 
Figure 9 
Best Percent Change in Sum of Target Lesion Dimension from Baseline ...........37 
Figure 10 Simulated Poziotinib Plasma Concentrations Following QD and BID Dosing ...38 
Figure 11 Study Design Diagram ..............................................................................................41 
Figure 12 Dose-Finding Diagram .............................................................................................42 
 
 


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1 INTRODUCTION 
1.1 Background 
1.1.1 Human Epidermal Growth Factor Receptor Family and Cancer 
The human epidermal growth factor receptor (EGFR) family consists of four receptor sub-type 
members: epidermal growth factor receptor (EGFR/HER1 or ErbB-1), HER2 (ErbB-2), HER3 
(ErbB-3), and HER4 (ErbB-4), all of which 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, which can promote cancer 
growth [1]. 
Several solid tumor 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 [2]. HER2 and other members of the EGFR receptor family are 
overexpressed in roughly 20% to 25% of breast cancers and is a prognostic marker [3, 4]. 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 [4, 5]. HER2 is also overexpressed in several other solid tumor 
malignancies. 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 Ministry of Health, Labour and Welfare (MHLW) and the US Food 
and Drug Administration (FDA) to treat patients with HER2-positive breast cancer, including 
trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) [3, 4].  
1.1.1.1 EGFR Exon 20 Mutation Non-Small Cell Lung Cancer  
Despite years of research and prevention strategies, lung cancer continues to be the most 
common cause of cancer-related deaths worldwide. Activating epidermal growth factor receptor 
(EGFR) mutations are key drivers of non-small cell lung cancer (NSCLC) in 10% to 15% of 
patients of European descent and approximately 40% of patients of East Asian descent [6].  
Patients with the most common activating EGFR mutations, exon 21 L858R and deletions in 
exon 19 (del19), typically have initial substantial response to therapy with EGFR tyrosine kinase 
inhibitors (TKIs) such as erlotinib, gefitinib or afatinib. In contrast, mutations in exon 20 of 
EGFR, which account for 5% to 10% of all EGFR mutations, have been generally associated 
with de novo resistance to EGFR TKIs. The reported response rate of patients with EGFR exon 
20 insertions to gefitinib and erlotinib is low at 5% with a median PFS of 1.5 months. A 
combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 clinical trials 
showed that the response rate to afatinib is 8.7% with a median PFS of 2.7 months in EGFR exon 
20 insertions patients [7]. This is in contrast with the activity of erlotinib, gefitinib, and afatinib 
in classical EGFR mutations where the response rate is 70% with a median PFS of 10-
13 months.  
The activity of other irreversible EGFR TKIs like neratinib and dacomitinib EGFR TKIs is 
limited for EGFR exon 20 mutations. In a Phase II trial of neratinib, three patients with exon 
20 EGFR insertions NSCLC did not have radiographic responses. In an initial Phase I trial of 


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dacomitinib, six patients with EGFR exon 20 insertions were included and only one (with 
delAsn770insGlyTyr) had a response [8]. 
1.1.1.2 HER2 Exon 20 Mutation Non-Small Cell Lung Cancer 
Human epidermal growth factor 2 (HER2 ErbB-2/neu) is a member of the ErbB receptor tyrosine 
kinase family. The ErbB2 gene, which encodes for HER2, is a major proliferative driver that 
activates downstream signaling through PI3K-AKT and MEK-ERK pathways. HER2 mutations 
consist of in-frame insertions in exon 20, leading to constitutive activation of the receptor and 
downstream AKT and MEK pathways [9]. 
HER2 mutations have been identified in approximately 1% to 4% of NSCLC. In an initial report, 
mutations in the HER2 kinase domain were identified in 4.2% of 120 primary NSCLC overall 
and 9.8% in adenocarcinomas. A subsequent study of 671 primary resected NSCLC, HER2 
mutations were found in 1.6% of samples overall, but in 3.9% of adenocarcinoma samples, and 
more frequently in Asian ethnicity [9]. The largest retrospective series published to date, 
comprising 65 patients with NSCLC and HER2 mutations, provides important insights into the 
clinic-pathological features and correlates: mutations were found exclusively in patients with 
adenocarcinoma subtype, and predominantly in female patients and non-smokers, a population 
similar to the EGFR-mutated NSCLC. 
There is no FDA approved targeted therapy[10] for HER2 exon 20 insertion mutation NSCLC. 
Chemotherapy remains the standard of care for metastatic disease with severe side effects and 
modest efficacy.  
Patients with HER2 mutated NSCLC treated with lapatinib, a pan HER inhibitor, experienced 
progressive disease. The most promising data to date have been obtained using irreversible TKIs 
targeting HER2/3 and EGFR, such as afatinib, neratinib and dacomitinib. Three out of eight 
HER2 mutant NSCLC patients treated with afatinib achieved a partial response. Dacomitinib 
demonstrated an overall 13% response rate in the 26 HER2-mutant patients [9].  
1.1.2 Poziotinib  
1.1.2.1 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 [2].  
1.1.2.2 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.  




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Figure 2 Poziotinib (HM781-36B) is a Potent Inhibitor of Cell Lines with EGFR Exon 20 
Insertions 
 
Figure 3 Effect of Poziotinib (HM781-36B) on EGFR Phosphorylation and Downstream 
Signaling 
 
In vivo studies were also conducted to test the effect of poziotinib in genetically-engineered mice 
with EGFR exon 20 insertion mutations. Mice were treated daily with vehicle or 10 mg/kg 
poziotinib for 4 weeks. Waterfall plots of tumor volume change as measured by MRI 
demonstrated approximately 80% tumor inhibition at 4 weeks (Figure 4) [11]. 








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1.1.2.4.2 Atypical HER2 Mutations 
Several atypical HER2 mutations that are sensitive to poziotinib in vitro have been identified 
[13]. Poziotinib was tested in Ba/F3 cell lines expressing selected atypical HER2 mutations. 
Poziotinib was active against all exons 19, 20, and 21 point mutations (Figure 8). Poziotinib was 
significantly more potent than either afatinib, neratinib, or tarloxotinib-TKI against HER2 exon 
19 and 20 mutations, but there was no significant difference in average IC50 for exon 21 
mutations.  
Although no studies have been conducted with poziotinib, activating HER2 mutations have been 
identified in other cancers. Both I655v [14] and I767M [15] have been found in breast cancer 
tumors and S310F [16], a mutation located in the extracellular region of HER2.  
Figure 8 Poziotinib Inhibits Growth of Atypical HER2 Mutant Ba/F3 Cell Lines 
  


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1.1.2.5 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 [17]. 
In vitro studies have shown that the solubility of poziotinib is pH dependent. Poziotinib is highly 
soluble at acidic pH, its solubility is significantly reduced at neutral or basic pH. Between 
pH 1-4, the solubility of poziotinib is 80 µg/mL whereas the solubility is less than 5 µg/mL at pH 
6.8 (data on file). Similar trends have been observed with other EGFR tyrosine kinase inhibitors 
such as erlotinib and gefitinib. Although the effect of pH on systemic exposure of poziotinib has 
not been established, based on the solubility profile, it is quite likely that the absorption of 
poziotinib could be lower at higher pH.  
Because proton pump inhibitors (PPIs), H2 histamine receptor antagonists, and antacids increase 
the gastric pH, we recommend that if possible, concomitant administration of long-acting PPIs or 
H2 receptor antagonists with poziotinib should be avoided, which is similar to the instructions 
for other TKIs. If needed, patients may take short acting antacids (e.g., Maalox®) at least 4 hours 
before or after poziotinib administration.  
1.1.2.6 Poziotinib Toxicity Studies  
The toxicity of single and repeated daily doses of oral poziotinib was 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 canine 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). There were no cardiovascular effects (electrocardiogram [ECG], blood 
pressure, heart rate, and QT interval) in poziotinib doses up to 0.15 mg/kg/day.  


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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. They 
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 
appetite, and pruritus. These toxicological effects observed in rats, dogs and humans with 
poziotinib mirror those observed with other EGFR inhibitors [18-21], 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 consistent with the results of 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. 
In addition, the photo-cytotoxicity of poziotinib was evaluated in BALB/c 3T3 clone A31 cells 
in the presence and absence of uv light. Based on the results of this study, poziotinib did not 
show any evidence of phototoxicity on BALB/c 3T3 clone A31 cells under the conditions of this 
study. 
1.1.3 Poziotinib Clinical Studies 
The clinical development program for poziotinib is ongoing in collaboration with Hanmi in 
Korea. To date, a total of 11 studies have been conducted in Korea, of which four are ongoing 
Investigator Initiated studies (IIS). Clinical studies completed in Korea include: 
• Two Phase 1 studies (HM-PHI-101 and HM-PHI-102) conducted in patients with 
advanced cancers (solid tumors) are PK/PD and dose finding studies. 
• Four Phase 2 studies (NOV120101-202, HM-PHI-A201, NOV12010-201, and 
NOV12010-203) conducted in patients with EGFR-mutant NSCLC, advanced gastric 
cancer and breast cancer (HER2 positive). 


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In the United States, the following poziotinib are ongoing: 
• A Phase 1 study (SPI-POZ-101) in HER2+ breast cancer in combination with T-DM1 
• A Phase 2 study (SPI-POZ-201) in HER2+ MBC with ≥2 prior HER2 directed therapies 
• A Phase 2 study (SPI-POZ-202) in NSCLC with EGFR or HER 2 exon 20 insertion 
mutation in pretreated and treatment naïve patients. 
• A US Investigator Initiated Study (IIS-POZ-001) in NSCLC with EGFR or HER2 exon 
20 insertion/mutation 
To date, more than 800 patients have received poziotinib monotherapy in open-label clinical 
trials and compassionate uses at doses ranging from 0.5 mg to 32 mg on an intermittent dosing 
schedule and from 8 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 response 
rates or prolonged stabilization of disease. Clinical benefit has been observed in patients with 
several solid tumors. 
1.1.3.1 Summary of Clinical Efficacy 
NOV120101-202 was a Phase 2, prospective, open-label, multicenter, exploratory study 
conducted in adult patients with Stage 3B or 4 NSCLC (including lung adenocarcinoma) with 
acquired resistance to first-generation EGFR TKIs (gefitinib or erlotinib). This study was 
conducted by Hanmi and National OncoVenture. Patients were not screened for EGFR or HER2 
exon 20 mutations.  
The primary study endpoint was Progression-free Survival (PFS). In addition, a number of 
secondary and exploratory endpoints were also assessed, including PFS rate at 16 weeks of 
treatment, Objective Response Rate (ORR), Disease Control Rate (DCR), overall survival (OS), 
time to progression (TTP), time to objective response, duration of objective response, duration of 
disease control, and change in quality of life: EQ visual analog scale (EQ VAS) and EQ-5D 
index to measure levels of mobility, self-care, activity, pain/discomfort, and anxiety/depression. 
Exploratory endpoints included a population PK profile and a subgroup analysis of genetic 
information confirmed from tumor tissue and blood samples. The primary and secondary 
endpoints of ORR and DCR are discussed in this section. 
Poziotinib was administered orally at a dose of 16 mg/day once daily for 28-day (4-week) 
continuous cycles until the patient exhibited PD or intolerable AEs that led to drug 
discontinuation. The planned enrollment for this study was 40 patients. Tumor response was 
assessed periodically at protocol-designated times. 
Forty patients were enrolled, and 39 patients were included in the Full Analysis Set and the 
Safety Analysis Set. One patient was not treated with poziotinib and was excluded from the 
analyses. The Per Protocol Analysis Set included 35 patients; 3 were excluded because of 
noncompliance with treatment, and 1 was excluded because of an inclusion criterion deviation. 
The majority of patients withdrew from the study due to PD or lack of efficacy (72.5%, 29/39) 
followed by withdrawal of consent (17.5%, 7/39), AEs (5%, 2/39), and other (2.5%, 1/39). 
In the Full Analysis Set, the majority of patients had an event, 87.18% (34/39) versus 92.31% 
(36/39), after independent and Investigator review, respectively. Regardless of the censoring rule 
used, the number of events remained uniform. The median PFS was 2.70 months by independent 


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review (regardless of censoring rule) versus 3.52 or 3.65 months by Investigator assessment with 
censoring Rule 1 and Rule 2, respectively. In the Per Protocol Analysis Set, 4 patients were 
removed from the analysis, but the results were similar to the results presented in the Full 
Analysis Set. 
1.1.3.2 Summary of Safety 
Patients in the completed poziotinib studies 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). Table 1 summarizes the most common (≥10%) treatment-
emergent AEs in the 4 mg, 8 mg, 12 mg, and 16 mg/day cohorts of Studies HM-PHI-101, 
HM-PHI-102, HM-PHI-A201, NOV120101-201, NOV120101-202, and NOV120101-203. 




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1.2 Rationale for the Current Study 
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 
demonstrated that poziotinib may be a good option for patients harboring these mutations. These 
data support the expectation that poziotinib will be efficacious and well tolerated in solid tumor 
patients that overexpress EGFR or HER2 or that harbor mutations in EGFR or HER2.  
Doses from 0.5 mg to 32 mg for 14 days of a 21-day cycle were evaluated in a Phase 1 study 
(HM-PHI-101) in Korean patients with advanced solid tumors. Grade 3 diarrhea was reported as 
a DLT in one patient each in the 12-mg, 16-mg, and 24-mg dose groups. Two patients had 
Grade 3 diarrhea in the 32-mg group. No DLTs were reported in patients given <12 mg 
poziotinib. The MTD was determined to be 24 mg for intermittent dosing.  
In another Phase 1 study (HM-PHI-102), Korean patients with advanced solid tumors were 
treated with doses of 12 mg, 18 mg, or 24 mg continuously for 28 days. One patient treated with 
18 mg poziotinib had a DLT of Grade 3 decreased appetite. A patient treated with 24 mg 
poziotinib experienced two DLTs of Grade 3 diarrhea and Grade 3 decreased appetite. None of 
the patients treated with 12 mg poziotinib experienced DLTs and it was determined that the 
MTD for continuous dosing was 18 mg.  
SPI-POZ-202 is an ongoing, multinational, Phase 2 study of poziotinib treatment in patients 
with locally advanced or metastatic lung cancer with EGFR or HER2 exon 20 insertion 
mutations. The starting dose for this study is 16 mg once daily. Enrollment into Cohort 1 
(previously treated patients with EGFR mutations) and Cohort 2 (previously treated patients with 
HER2 mutations) in that study has been completed. Preliminary data from Cohort 1 for the 
primary endpoint (ORR) have been analyzed.  
Cohort 1 enrolled a total of 115 patients who received 16 mg/day of poziotinib. The Intent-to-
Treat analysis showed that 17 patients had a response (by RECIST) and 62 patients had stable 
disease for a 68.7% disease control rate (DCR). The confirmed objective response rate (ORR) 
was 14.8% (95% CI; 8.9%-22.6%). The median duration of response was 7.4 months. The best 
change in target lesion dimensions from Baseline is presented in Figure 9. The safety profile was 
at the high end of expected toxicities but in-line as to type of AE with other second-generation 
EGFR tyrosine kinase inhibitors. Permanent drug discontinuation related to AEs was seen in 
only 10% of patients but temporary drug interruption was seen in 88% of patients and dose 
reduction was seen in 68% of patients as permitted by protocol. 




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Figure 10 Simulated Poziotinib Plasma Concentrations Following QD and BID Dosing 
 
2 STUDY OBJECTIVES  
2.1 Primary Objective 
To evaluate the following in NSCLC patients treated with poziotinib:  
• Phase 1: Dose-Finding - Maximum Tolerated Dose (MTD) or Maximum 
Administered Dose (MAD)  
• Phase 2: Efficacy - Objective Response Rate (ORR)  
2.2 Secondary Objectives 
• Phase 1: Dose-Finding 
• 
Pharmacokinetics of poziotinib and M1 and M2 metabolites 
• 
Safety and Tolerability 
• Phase 2: Efficacy 
• 
Disease Control Rate (DCR) 
• 
Duration of Response (DoR) 
• 
Progression-Free Survival (PFS)  
• 
Pharmacokinetics of poziotinib and M1 and M2 metabolites 
• 
Safety and Tolerability 
2.3 Exploratory Objective 
• 
Overall Survival 


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3 INVESTIGATIONAL PLAN 
3.1 Study Design and Treatment Plan 
This is a Phase 1/2, open-label, multicenter dose finding study to determine the MTD/MAD of 
poziotinib when administered once daily (QD) or twice daily (BID) to Japanese participants with 
locally advanced or metastatic NSCLC.  
3.1.1 Phase 1: Dose-Finding 
Phase 1 is a dose finding study with two parallel, randomized dose groups. Each group will 
undergo dose-finding scheme using a 3+3 design with the assessment of dose-limiting toxicities 
(DLTs) at up to three dose levels. Patients will be hospitalized for the first 2 weeks of Cycle 1.  
• Group 1 (once daily dosing [QD]): Starting dose of 8 mg. 
• Group 2 (twice daily dosing [BID]): Starting dose of 4 mg BID. 
The DLT assessment will be conducted in Cycle 1 of the Phase 1 of the study. Poziotinib dose-
finding will proceed based on the occurrence of DLTs during Cycle 1. Although DLTs will be 
evaluated based on the list of criteria specified below, toxicity related to the onset of any 
unexpected adverse events will be evaluated as well in addition to the DLTs. The MTD or MAD 
will be determined in each group independently. The DLTs for MTD/MAD will be assessed by 
the Medical Monitor in consultation with the site Principal Investigator. In addition to the 
defined DLTs, dose advancement/MTD will be decided based on all safety information, 
including adverse events that the subject experiences that are not defined as DLTs. A DLT will 
be any of the following treatment-related adverse events that occur during Cycle 1, despite 
optimal medical supportive therapy: 
• Non-Hematological Toxicity:  
• 
Grade 3 or higher toxicity based on NCI-CTCAE (version 5.0), except for alopecia 
• 
Grade 3 or higher nausea and vomiting, despite treatment with oral anti-emetics at the 
highest dose 
• 
Grade 3 or higher diarrhea, despite diarrhea treatment at the highest dose 
• Hematological Toxicity: 
• 
Grade 4 or higher neutropenia (ANC<0.5×109/L) sustained for 7 days or more 
• 
Febrile neutropenia (ANC<1.0×109/L with a single temperature of >38.3°C (101.0°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than one hour) 
• 
Neutropenic infection: Grade 3 or higher infection accompanying Grade 4 
neutropenia (ANC<0.5×109/L) (requiring IV antibiotic, antifungal or antiviral agent 
administration/ requiring radiation or surgical therapy) 
• 
Grade 4 thrombocytopenia (PLT<25,000/mm3) or any grade thrombocytopenia 
requiring platelet transfusion  
However, in case of ANC<0.5×109/L, conduct a repeat test on at least the 7th day in order to 
verify if it is lasted for 7 days or more. 
Because Phase 1 is for DLT assessment and dose finding, poziotinib dose modifications are not 
permitted during Cycle 1 in Phase 1. Dose modifications are permitted beginning with Cycle 2 


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based on Sponsor recommendations. Patients who discontinue from the study for reasons other 
than DLTs will be replaced. 
3.1.2 Phase 2: Efficacy 
Once the MTD/MAD is determined, 40 additional NSCLC patients with EGFR (20 patients) or 
HER2 (20 patients) exon 20 insertion mutations (including duplication mutations) will be 
enrolled to evaluate the efficacy of poziotinib at the dose and regimen determined in Phase 1. 
The choice of QD or BID for Phase 2 will be determined by the sponsor when Phase 1 of the 
study is complete. If the patient is EGFR positive, then they go in the EGFR group. If the patient 
is HER2 positive, then they go in the HER2 group. Dose modifications are permitted based on 
Sponsor recommendations and notification of the Medical Monitor. 
During each 28-day cycle, patients who are eligible for participation will receive poziotinib at 
the assigned dose, orally, QD or BID depending on the dosing group, continuously. All patients 
will be treated for up to 24 months or until disease progression, death, intolerable adverse events 
(AEs), or other protocol-specified reasons for patient withdrawal.The study design diagram in 
presented in Figure 11, the dose-finding diagrams are presented in Figure 12, and the schedule 
of study assessments and procedures is presented in Appendix 1 for Phase 1 and in Appendix 2 
for Phase 2. 






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3.2 Study Duration  
It is estimated that the first patient will be enrolled in January 2020 and the last patient visit will 
occur approximately March 2025.The duration of study participation for each patient, in general, 
includes the following segments:  
• Screening Period: up to 30 days 
• Treatment Period: 28 days per cycle for up to 24 months of treatment or until disease 
progression, death, intolerable adverse events (AEs), or other protocol-specified reason 
for patient withdrawal  
• Safety Follow-up Visit: 35 (±5) days after the last dose of poziotinib  
• Long-Term Follow-up: After study drug discontinuation, patients who have consented 
will be contacted every 3 months, for up to 2 years after patient’s first dose of poziotinib, 
for survival assessment 
4 PATIENT POPULATION  
4.1 Inclusion Criteria  
1. Patient is at least 20 years of age  
2. Patient must be willing and capable of giving written Informed Consent, adhering to 
dosing and visit schedules, and meeting all study requirements  
3. Phase 2: If an archival tissue sample is not available, a tumor biopsy will be required.  
4. Previously treated patient with histologically or cytologically confirmed (archival tissue 
accepted) locally advanced or metastatic non-small cell lung cancer (NSCLC) and is not 
a candidate for definitive therapy  
• 
Phase 1: No test for mutational status is required  
• 
Phase 2: Documented EGFR or HER2 exon 20 insertion mutation (including 
duplication mutations) in NSCLC patients. Patients will be enrolled based on 
documentation of mutational status using PCR or a validated next generation 
sequencing detection analysis test.  
• 
Documented EGFR exon 20 insertion mutation, including D770_N771insSVD, 
D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other 
EGFR exon 20 in-frame insertion mutation (including duplications).  
• 
Documented HER2 exon 20 insertion mutation, including A775_G776insYVMA, 
G776_V777insVC, or P780_Y781insGSP, or any other HER2 exon 20 in-frame 
insertion mutation (including duplications).  
5. Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid 
Tumors (RECIST, version 1.1). Metastatic lesions in bone, CNS, or in brain cannot be 
used for target lesions.  
6. Prior treatment status: 
• 
Phase 1: Patient with refractory NSCLC to available standard therapies  
• 
Phase 2: Progression after at least one systemic therapy for locally advanced or 
metastatic disease 
7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1  


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8. Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for 
non-hematologic toxicities (except for Grade ≤2 peripheral neuropathy) and has adequate 
hematologic, hepatic, and renal function at Baseline, as defined by: 
• 
Leukocytes ≥3.0×109/L 
• 
Absolute neutrophil count (ANC) must be ≥1.5×109/L  
• 
Platelet count ≥100×109/L 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤2 mg/dL; if hepatic metastases are present, ≤2.5×ULN  
• 
SGOT (AST) and SGPT (ALT) ≤2.5×ULN with the following exception; Patients 
with liver metastases AST, ALT ≤5×ULN  
9. Patient is willing to practice 2 forms of contraception, one of which must be a barrier 
method. Female patients of childbearing potential must use an effective method of birth 
control (e.g., oral contraceptive, intrauterine device, bilateral tubal ligation/occlusion, 
condoms, or diaphragm, not engaging in sexual intercourse) during treatment period and 
3 months thereafter. Males must use an effective method of birth control (e.g., condoms, 
vasectomy, not engaging in sexual intercourse) during treatment period and 3 months 
thereafter.  
10. Females of childbearing potential must have a negative pregnancy test within 7 days prior 
to Day 1. Females who are postmenopausal for at least 1 year (defined as more than 
12 months since last menses) with no other medical reasons or who are surgically 
sterilized do not require this test. 
4.2 Exclusion Criteria 
1. Phase 2 : Patient has EGFR T790M mutation or any other acquired EGFR exon 20 point 
mutation  
2. Phase 2 : Patient has had previous treatment with poziotinib. The currently approved 
TKIs that are not considered to be exon 20 insertion-selective are permissible.  
3. Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer 
treatment; systemic anti-cancer treatment or investigational treatment should not be used 
within 2 weeks prior to Cycle 1, Day 1;local radiation therapy for bone pain may be 
allowed.  
4. Patient has used strong inhibitors/inducers of CYP3A4 and CYP2D6 within 1 month 
prior to Cycle 1, Day 1.  
5. Patient has brain metastases and is clinically symptomatic, requires high dose or 
increasing doses of systemic corticosteroids, or needs any anticonvulsant therapy for 
metastatic brain disease.  
6. Patient has a high risk for or 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. Cardiac ejection fraction <50% as 
determined by either echocardiogram (ECHO) or multi-gated acquisition (MUGA) 
during Screening.  


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7. Patient has had another primary malignancy within 3 years prior to starting study 
treatment, except for adequately treated basal or squamous cell carcinoma of the skin or 
cancer of the cervix in situ  
8. 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 
5.0) Grade 2 or above diarrhea due to other etiologies) 
9. Patient has an active Grade ≥2 skin disorder, rash, mucositis, or skin infection that needs 
medication or therapy or existing Grade ≥2 skin toxicity from previous therapies; 
Grade >2 neuropathy, Grade ≥2 pneumonitis.  
10. 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  
11. 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). Patient 
has active HBV or HCV infection. 
12. Patient is HIV antibody positive. 
13. Patient currently has or has had interstitial lung disease in the past 
14. Patient has known hypersensitivity to poziotinib or has a history of allergic reactions 
attributed to chemically similar compounds or other tyrosine kinase inhibitors (TKIs)  
15. Patient has an active uncontrolled infection, underlying medical condition, or other 
serious illness that would not be appropriate for this study  
16. Patient has unstable, uncontrolled, active bleeding disorders that the investigator 
considers that the patient could be at increased risk or not be suitable for treatment in this 
study  
17. Patient is pregnant. 
18. Women who are breastfeeding or women who are not willing to stop breastfeeding 
during study treatment period and for 30 days after the last dose of study drug. 
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 study drug administration 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 >28 days since last poziotinib administration 
• Investigator decision 
• Sponsor decision 


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• 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 
withdrawn from treatment will return for a Safety Follow-up Visit 35 (±5) days after the last 
dose of poziotinib or prior to beginning a new treatment, whichever is first. If death is recorded 
as the reason for study discontinuation, the cause of death should be recorded on the CRF. 
After study drug discontinuation, patients who have consented will be contacted every 3 months, 
for up to 2 years after patient’s first dose of poziotinib, for survival assessment. 
All patients will be withdrawn from the Long-Term Follow-up for the following reasons:  
• Patient withdrawal of informed consent 
• Investigator decision 
• Sponsor decision 
• Lost to follow-up 
• Death 
5 STUDY PROCEDURES  
The Schedules of Study Assessments and Procedures is presented in Appendix 1 and  
Appendix 2. 
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 undergo a Screening Visit and eligibility 
determined up to 30 days prior to Day 1. 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 may be allowed for use as a Screening Assessment with Sponsor’s approval. 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 and Appendix 2 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 Patient ID according to the instructions provided in the study binder.  
Confirmation of eligibility is to be received by the investigational site from Spectrum or 
designated Contract Research Organization (CRO) 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 


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code and a 3-digit patient sequential number, unique to a site, separated by a hyphen 
(ie, JP001-001).  
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 Visit 
Informed Consent must be obtained prior to any study procedures. The following assessments 
should be performed at the Screening Visit within 30 days of Day 1.  
• Verify existing pathology and tissue-based mutation diagnostic records, and available 
imaging test reports from medical records before consenting the patient. Tumor 
assessment scans for eligibility assessment must be completed within 4 weeks of Cycle 1, 
Day 1.  
• Informed Consent 
• Patient ID 
• Relevant medical history 
• Demographic data 
• Height and weight 
• Complete physical examination, including auscultation  
• Vital signs 
• Resting O2 saturation  
• Pulmonary function assessment (Chest X-ray and pulmonary function test) 
• Eastern Cooperative Oncology Group (ECOG) Performance Status assessment 
• Pregnancy test (beta human chorionic gonadotropin [β-HCG]) in women of childbearing 
potential 
• Hepatitis B tests (surface antigen, core antibody, and surface antibody) 
• Hepatitis C antibody test 
• HIV antibody test 
• Screening/Baseline tumor assessment within 4 weeks prior to Cycle 1, Day 1 
• Baseline brain MRI scan for patients with known brain metastases (if needed)  
• Tissue and whole blood collection 
• 
Phase 2 only: Tissue sample (archival sample or tissue biopsy) for genotyping 
• 
Phase 2 only: Whole blood sample for plasma circulating tumor DNA (ctDNA) 
analysis  
• 
All patients: Whole blood sample for CYP2D6 genotyping (metabolic profile 
analysis) 
• Complete blood count (CBC) with 5-part differential and platelets prior to poziotinib 
administration (may be obtained up to 14 days prior to Cycle 1, Day 1)  
• Serum chemistry, including KL-6 and C-reactive protein (may be obtained up to 14 days 
prior to Cycle 1, Day 1)  


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• 12-lead electrocardiogram (ECG)  
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction (ECHO or MUGA 
results within 6 months prior to Cycle 1, Day 1 is acceptable if there is no major known 
cardiac event during this period) 
• Adverse event assessment using NCI CTCAE, version 5.0, record SAEs before the first 
dose of poziotinib 
• Concomitant medications  
5.3.2 Treatment Period – Cycle 1, Day 1  
• Eligibility confirmation 
• Admission to hospital (Phase 1 – Dose-Finding only) 
• Weight  
• Physical examination 
• Vital signs  
• Resting O2 saturation  
• Pulmonary function assessment (if not evaluated within the past 6 months) 
• ECOG Performance Status assessment 
• Pregnancy test in women of childbearing potential (if Screening pregnancy test was more 
than 7 days prior to Day 1)  
• CBC with 5-part differential and platelets prior to poziotinib administration. If the 
Screening CBC is within 14 days of Cycle 1 Day 1, the Day 1 CBC test is not required. 
• Serum Chemistry (including KL-6 and C-reactive protein if not assessed during 
Screening). If the Screening Serum Chemistry is within 14 days of Cycle 1 Day 1, the 
Day 1 test is not required. 
• 12-lead ECG predose and at 1 hour and 2 hours (±15 min) postdose 
• Pharmacokinetic blood sampling: 
• 
Phase 1: Intensive PK blood samples drawn predose and 30 minutes, 1 and 2 hours 
(±15 minutes) postdose, and 3, 4, 6, 8, 12, 14 (±30 minutes) postdose, and 24 hours 
(±1 hour) postdose 
• 
Phase 2: Sparse PK blood sampling taken predose and at 1 hour and 2 hours 
(±15 min) postdose  
• Dispense poziotinib  
• Dispense supportive care medications as needed  
• Adverse event assessment using NCI CTCAE, version 5.0  
• Concomitant medications review 
• Patient Diary dispensed 
5.3.3 Phase 1, Cycle 1, Days 2-14, in the Hospital 
The following evaluations will be done on Days 7, and 14: 


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• Physical examination 
• Vital signs  
• Resting O2 saturation  
• Pulmonary Function Assessment 
• ECOG Performance Status assessment 
• CBC with 5-part differential and platelets,  
• Serum Chemistry  
• ECGs (predose) 
• Pharmacokinetic blood sampling (Day 13 only): 
• 
Intensive PK blood samples drawn 
• Predose  
• 30 minutes, 1 and 2 hours (±15 minutes) postdose 
• 3, 4, 6, 8, 12, and 14 hours (±30 minutes) postdose 
• 24 hours (±1 hour) postdose 
• Adverse event assessment using NCI CTCAE, version 5.0 
• Concomitant medications 
• Discussion and assessment of breathing signs and symptoms; assessment of pulse 
oximetry measurements 
5.3.4 Criteria for Discharge After Day 14 During DLT Evaluation Period (Phase 1 only) 
The patient must meet the following criteria for hospital discharge after Day 14 during the DLT 
evaluation period: 
• In the Investigator's clinical judgement, the patient is healthy enough to be discharged 
based on the evaluations in Section 5.3.3. 
• 
If the patient doesn't acceptably pass all evaluations in Section 5.3.3, the patient must 
continue to be hospitalized until reaching the criteria in Section 5.3.4 or complete the 
DLT evaluation period (1 cycle). Only the assessments that the patient didn’t pass to 
be discharged need to be repeated in order to be discharged. It is unnecessary to 
recheck all evaluations. 
• The investigator has documented all evaluations and assessments on the medical record. 
• Adverse events have returned to Grade <1 or Baseline level 
• No ongoing SAE. 
• It has been established that the patient has access to emergency medical care. If the 
patient lives far from the clinical site or has difficulty traveling to the site, it has been 
confirmed that the site and neighborhood medical institution are well-cooperated. 
• It has been confirmed that family or caregiver cooperation is established.  
• The patient has been instructed on how to contact the study physician and site. Patients 
will receive a study information card, including information for 24-hour contact access to 
the physician and the study site.  


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5.3.5 Phase 2, Cycle 1, Day 8 and 15 (±2 days) (Phase 2 Only)  
• Physical examination 
• Vital signs  
• Resting O2  Saturation 
• Pulmonary Function Assessment 
• ECOG Performance Status assessment 
• Adverse event assessment using NCI CTCAE, Version 5.0  
• Concomitant medications  
• Dispense supportive care medications as needed  
• Review patient diaries  
5.3.6 Treatment Period - Telephone Contact (Both Phases)  
Cycle 1, Day 22 (±2 days) 
Cycle 2 - Days 8, 15, and 22 (±2 days) 
Cycles 3+ - Day 15 (±2 days)  
• Adverse event assessment using NCI CTCAE, Version 5.0  
• Concomitant medications  
5.3.7 Treatment Period Office Visit – Cycle 2+, Day 1  
• 
Weight  
• 
Physical examination  
• Vital Signs 
• Resting O2 Saturation  
• 
ECOG Performance Status assessment  
• Pregnancy test in women of childbearing potential  
• Complete blood count with 5-part differential  
• Serum chemistry, including KL-6 and C-reactive protein 
• Imaging Session  
• 
Tumor assessment (to be performed at approximately 4 weeks (Cycle 2, Day 1 [up to 
Cycle 2, Day 10]), 8 weeks (Cycle 3, Day 1 [up to Cycle 3, Day 10, with at least 28 
days from previous tumor assessment]), and approximately every 8 weeks 
[±10 days)]thereafter) 
• 
Whole blood samples (20 mL) on Cycle 2, Day 1, Cycle 3, Day 1, and then every 8 
weeks  
• 
Pulmonary Function Assessment  
• 12-lead ECG prior to that day’s patient dose and 1 and 2 hours postdose (Cycle 2 only) 


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• Pharmacokinetic blood sampling (4 mL): 
• 
Phase 2: Predose and 1 and 2 hours postdose (±15 minutes) samples drawn on 
Cycle 2, Day 1 only and predose on Cycle 3, Day 1 and then every 8 weeks. 
• Collect and dispense poziotinib  
• Dispense supportive care medications as needed  
• Adverse event assessment using NCI CTCAE, Version 5.0  
• Concomitant medications  
• Patient Diary collected and dispensed  
5.3.8 Safety Follow-up/End-of-Study Visit (35 [±5] Days after Last Dose of Study 
Treatment) 
The Safety Follow-up Visit is required 35 (±5) days after the last dose of poziotinib is 
administered. The following assessments are to be performed at this visit:  
• Weight  
• Physical examination 
• Vital signs  
• Pulmonary Function Assessment and Resting O2 Saturation 
• ECOG Performance Status assessment 
• Pregnancy test in women of childbearing potential  
• Tumor assessment (unless the patient has documented disease progression or has 
undergone a tumor assessment within the previous 8 weeks)  
• Complete blood count with 5-part differential 
• Serum chemistry, including KL-6 and C-reactive protein 
• 12-lead ECG  
• Newly biopsied tumor tissue taken from patients who progress (optional, but highly 
encouraged) (Phase 2 only) 
• Whole blood samples for plasma ctDNA analysis if the patient progresses (optional) 
(Phase 2 only) 
• Adverse event assessment using NCI CTCAE, Version 5.0  
• Concomitant medications 
• Patient diary collected 
5.3.9 Long-Term Follow-up – Every 3 Months  
• After study drug discontinuation, patients will be contacted every 3 months, for up to 2 
years after patient’s first dose of poziotinib, for survival assessment.  


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5.4 Description of Study Assessment Parameters 
5.4.1 Relevant Medical History 
At Screening, the patient’s relevant medical history, including type of cancer, HER2 and EGFR 
status (optional in Phase 1), history of tobacco use, previous therapies, and current medications 
will be collected.  
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 
Safety Follow-up Visit. Symptom-directed examinations are required at other visits. In addition, 
physical examination will be done on days 7 and 14 of Cycle 1 while Phase 1 patients are in the 
hospital, and Cycle 1, Days 8 and 15 for Phase 2 patients. Physical examinations are to be 
completed by a physician or other health professional licensed to perform such examinations. 
Findings will be documented in the patient’s medical record and on the appropriate CRF 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 Safety Follow-up Visit. In addition, 
vital signs will be taken on days 7 and 14 of Cycle 1 while Phase 1 patients are in the hospital, 
and Cycle 1, Days 8 and 15 for Phase 2 patients the patient is in the hospital. Heart rate and 
blood pressure will be recorded before poziotinib administration. 
5.4.4 Pulmonary Function and Resting Oxygen Saturation 
During the Screening Period the patient will be assessed for cofactors that may predispose to the 
development of pneumonitis including previous pneumonitis including radiation pneumonitis, 
radiation therapy to the lung fields, prior extensive chemotherapy, prior checkpoint inhibitor 
therapy, and connective tissue disease (rheumatoid arthritis, scleroderma, LES).  
In Phase 1, resting O2 saturation will be assessed at Screening, daily for the first 2 weeks of 
Cycle 1, while the patient is hospitalized, on Day 1 of all subsequent cycles, and at the Safety 
Follow-up Visit. In Phase 2, resting O2 saturation will be assessed at Screening, Cycle 1, Days 1, 
8, and 15, on Day 1 of all subsequent cycles, and at the Safety Follow-up Visit. 
In both phases, screening and monitoring for evidence of interstitial lung disease (ILD) by verbal 
discussion with the patient regarding breathing signs and symptoms, physical examination 
including auscultation, and pulmonary function tests (spirometry) will be performed.  
• In Phase 1, pulmonary function will be assessed at Screening, on Day 1 of Cycles 1-3, 
every 8 weeks thereafter, and at the Safety Follow-up Visit. In addition, evidence of ILD 
will be assessed on Cycle 1, Days 7 and 14 while the patient is in the hospital. 
• In Phase 2, pulmonary function will be assessed at Screening, on Day 1 of Cycles 1-3, 
every 8 weeks thereafter, and at the Safety Follow-up Visit. In addition, evidence of ILD 
will be assessed on Cycle 1, Days 8 and 15.  


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5.4.5 ECOG Performance Status 
Patients’ Performance Status will be evaluated using criteria as developed by the Eastern 
Cooperative Oncology Group (Appendix 3) at Screening and Day 1 of each cycle and at the 
Safety Follow-up Visit. In addition, in Phase 1, ECOG will also be evaluated on days 7 and 14 of 
Cycle 1 while the patient is in the hospital and in Phase 2 will be assessed on Cycle 1, Days 8 
and 15. 
5.4.6 Tumor Assessment 
Results of standard-of-care tests or examinations performed within 28 days prior to Cycle1, Day 
1 may be used for the Screening/Baseline tumor assessment. Tumor assessments must be 
performed using computed tomography (CT), positron emission tomography (PET)/CT, or 
magnetic resonance imaging (MRI). The image will be reviewed by a local radiologist as the 
Baseline image for response assessment and per the Investigator’s standard of care. 
For patients with known brain metastases, a Baseline brain MRI scan (within 28 weeks prior to 
Cycle 1, Day1) will also be performed to assess the status of brain metastases if present.  
Tumor assessments will also be performed at 4 weeks (Cycle 2, Day 1 [up to Cycle 2, Day 10]), 
8 weeks (Cycle 3, Day 1 [up to Cycle 3, Day 10, with at least 28 days from previous tumor 
assessment]), and then every 8 weeks (±10 days) for up to 24 months or until disease 
progression, death, intolerable adverse events (AEs), or other protocol-specified reasons for 
patient withdrawal or for a maximum of 24 months. 
Tumor assessment will be performed at the Safety Follow up Visit unless the patient has 
documented disease progression or has undergone a tumor assessment within the previous 8 
weeks. 
Each subsequent tumor assessment must use the same baseline radiographic technique, either 
CT, PET/CT, or MRI. Tumor assessments will be made according to RECIST criteria, 
Version 1.1 [22] using appropriate radiographic imaging or other techniques. For radiographic 
assessment, CT, PET/CT, or MRI must be performed at every assessment. Patient enrollment 
and clinical decisions will be based on local review.  
Measurable and non-measurable lesions that will not be followed by radiographic methods 
should be documented appropriately.  
5.4.7 Tissue, Plasma, and Whole Blood Samples  
Tissue and plasma samples (for mutational detection) are not required for patients in Phase 1 of 
the study. 
5.4.7.1 Tissue and Whole Blood Samples 
Tissue (Phase 2 Only): A tissue sample is required prior to Cycle 1, Day 1. If an archival tissue 
sample is not available, a tumor biopsy will be required.  
The tissue from the biopsy will be processed according to site procedures into a Formalin-Fixed 
Paraffin-Embedded (FFPE) block. A tissue sample collected at disease progression is optional. 
Embedded tumor tissue will be shipped to the central laboratory and stored at room temperature. 
DNA and/or RNA will be extracted from FFPE samples and subjected NGS mutational detection 
analysis (companion diagnostic development and resistance mechanism study).  


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5.4.7.2 Whole Blood Samples 
• Phase 1 and Phase 2: Whole blood samples (4 mL) will be collected once at Screening 
for CYP2D6 genotyping (metabolic profile analysis). Whole blood samples will be 
shipped at room temperature.  
• Phase 2 only: Whole blood samples (20 mL) will be drawn for plasma ctDNA analysis at 
Screening and when the patient progresses (collecting a sample at progression is optional 
but is highly encouraged). Blood samples will be processed at the site and shipped to the 
lab for storage at -70°C until ready for testing (companion diagnostic development and 
resistance mechanism study). Blood samples will also be collected on Day 1 of Cycles 2 
and 3 and then every 8 weeks thereafter in order to correlate poziotinib concentrations 
with ctDNA and efficacy.  
5.4.7.3 Sample Retention 
All samples will be banked at the lab for 5 years or for the duration that is compliant with local 
law. After this time, if no further analysis is planned, the Sponsor will request that the samples be 
destroyed as per local storage procedures.  
Banked samples will not be returned to the patient for any reason, even if the patient withdraws 
consent during the term of the study or after the patient withdraws from the study. These samples 
will be destroyed as described above or upon the request for destruction from the subject. In 
addition, even if the patient withdraws consent to use/store the optional samples while 
participating in this study, the patient can continue participating in this study if they wish. 
Genetic testing results will not be provided to patients unless requested by patients’ physicians. 
5.4.8 Pharmacokinetics 
Phase 1: The pharmacokinetics of poziotinib and M1 and M2 metabolites evaluated. Patient will 
have intensive PK blood samples drawn (4 mL whole blood each time point) on Cycle 1, Day 1 
and Cycle 1, Day 13 at the following timepoints: 
• Predose  
• Postdose 
• 
30 minutes, 1, and 2 hours (±15 minutes) 
• 
3, 4, 6, 8, 12, and 14 hours (±30 minutes) 
• 
24 hours (±1 hour) 
In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, 
mucositis, diarrhea, pneumonitis), PK blood samples will be collected as soon as possible 
following the onset of the AE, and the time of the last dose and the time of blood draw should be 
recorded. 
Phase 2: All patients will have blood samples drawn predose and at 1 hour and 2 hours (±15 
min) postdose for sparse PK sampling and time-matched concentration- ECG analysis on Day 1 
of Cycle 1 and Day 1 of Cycle 2 for time-matched concentration- ECG analysis. In addition, if a 
patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, 
pneumonitis), blood samples will be collected as soon as possible following the onset of the AE 
and the time of the last dose and the time of blood draw should be recorded. Blood samples will 


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also be collected predose on Cycle 3, Day 1 and every 8 weeks thereafter in order to correlate 
poziotinib concentrations with ctDNA and efficacy; the time of the last dose and the time of 
blood draw should be recorded.  
5.4.9 Clinical Laboratory Tests 
On Day 1 of each 28-day cycle, the patient’s absolute neutrophil count (ANC) must be 
≥1.5×109/L and platelet count must be ≥100×109/L before administering poziotinib. 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 of each 
cycle, and at the Safety Follow-up Visit. In addition, CBC will be done on Days 7 and 14 
of Cycle 1 while the patient is in the hospital. The results of the laboratory assessments 
should be evaluated and medically accepted by the responsible physician before the start 
of each cycle. If the Screening Visit is within 14 days of Day 1, the Day 1 CBC test is 
not required.  
• Chemistry Panel: A comprehensive chemistry and electrolytes, including blood urea 
nitrogen (BUN), AST/SGOT, ALT/SGPT, alkaline phosphatase (ALP), total bilirubin, 
albumin, calcium, lactate dehydrogenase, sodium, potassium, chloride, phosphate, 
magnesium, creatinine, glucose KL-6, and C-reactive protein, will be performed at 
Screening, Day 1 of each cycle, and at the Safety Follow-up Visit. If the Screening Visit 
is within 14 days of Day 1, the Day 1 serum chemistry panel is not required. In 
addition, a chemistry panel will be done on Days 7 and 14 of Cycle 1 while the patient is 
in the hospital. 
• 
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 or plasma β-hCG test will be performed at Screening, Cycle 1, 
Day 1 (if the Screening pregnancy test was more than 7 days prior to Day 1), Day 1 of 
each cycle, and at the Safety Follow-up Visit for all women of childbearing potential. 
5.4.10 Hepatitis B, Hepatitis C, and HIV Tests 
Tests will be for hepatitis B surface antigens and hepatitis B core and surface antibodies. If the 
hepatitis B surface antigen test is positive, the patient will be excluded from the study. If only the 
hepatitis B core antibody and/or hepatitis B surface antibody is positive, a serum hepatitis HBV 
DNA test will be done. If this test is positive the patient is excluded from the study. 
If hepatitis C antibody test is positive, an HCV RNA test will be done. If this test is positive, the 
patient is excluded from the study. 
Whole blood sample is used for the HIV test. If this test is positive the patient is excluded from 
the study. 


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5.4.11 Electrocardiogram  
A 12-lead ECG will be performed at Screening, predose and at 1 hour and 2 hours (±15 min) 
postdose on Cycle 1, Day 1 and Cycle 2, Day 1 for time-matched concentration-ECG analysis, 
and at the patient’s Safety Follow-up Visit. For Phase 1 patients, ECG will be performed predose 
on Days 7 and 14 of Cycle 1 while the patient is in the hospital. All ECGs will be sent for central 
analysis.  
5.4.12 Cardiac Ejection Fraction 
Cardiac ejection fraction will be assessed by either echocardiogram or multi-gated acquisition 
(MUGA) scan at Screening, and the Investigator can order subsequent tests based on patient 
standard of care. Results within 6 months prior to Cycle 1, Day 1 is acceptable if there is no 
major known cardiac event during this period. 
5.4.13 Concomitant Medications 
All medications administered from Screening to the Safety Follow-up Visit will be recorded on 
the CRF. A concomitant medication is any medication a patient is using from Cycle 1, Day 1 to 
the Safety Follow-up Visit. Poziotinib is not considered a concomitant medication. 
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. Patients may 
continue to use any ongoing medications not prohibited by the protocol. 
All prescription and over-the-counter medications at trial entry as well as any new medications 
started during the trial must be documented on the CRF and in the source documents. The 
documentation should continue until 35 (±5) days after the last dose of poziotinib. 
Premedications (such as antiemetics) used for supportive care are allowed as per institutional 
standards or guidelines and Investigator discretion. 
Other supportive and palliative therapies may be allowed during the study upon prior 
authorization from Sponsor’s Medical Monitor.  
5.4.13.1 Possible Drug Interactions 
Poziotinib is a substrate for cytochrome P450 (CYP) 3A4 and 2D6 enzymes. Patients may be 
taking medications that are strong inhibitors or inducers of these two enzymes (Table 2). The 
plasma concentration of poziotinib could be different in these patients. The Investigator should 
try to substitute a medication that is not a strong inhibitor/inducer of these enzymes, if possible. 
If there is not an available substitute for a medication that a patient is taking, or the patient is not 
willing, to change medications, the Investigator must monitor the patient closely for possible 
AEs or changes in response.  
Poziotinib is also a moderate inhibitor of CYP2C8 and CYP2D6; patients who take medications 
that are sensitive substrates for these two enzymes (Table 2) should be followed closely for 
possible changes in the patient’s response to these medications. Patients should be told to avoid 
grapefruit juice, Seville oranges, and St. John’s Wort during the study treatment. 




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5.4.13.5 Drugs that Affect Gastric pH 
In vitro studies have shown that the solubility of poziotinib is pH dependent. Poziotinib is highly 
soluble at acidic pH, its solubility is significantly reduced at neutral or basic pH. Although the 
effect of pH on systemic exposure of poziotinib has not been established, based on the solubility 
profile, it is quite likely that the absorption of poziotinib could be lower at higher pH.  
Because proton pump inhibitors (PPIs), H2 histamine receptor antagonists and antacids increase 
the gastric pH, we recommend that if possible, concomitant administration of long-acting PPIs or 
H2 receptor antagonists with poziotinib should be avoided, which is similar to the instructions 
for other TKIs. If needed, patients may take short-acting antacids (e.g., Maalox®) at least 4 hours 
before or after poziotinib administration. Patients should also avoid drink water that is alkaline.  
5.4.13.6 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  
5.4.14 Patient Discharge 
All patients in the Phase 1 dose-finding phase will be hospitalized for at least 14 days from 
Cycle 1, Day 1 of the study. In order to be discharged from the hospital, the patient must not 
have any ongoing SAEs or DLTs, and in the Investigator’s judgement, the patient is healthy 
enough to be discharged. At the discretion of the Investigator, the patient may continue to be 
hospitalized after Day 14 if in his or her clinical judgement this would be in the best interest of 
the patient. Hospitalization may continue for as long as medically necessary. Prior to patient 
discharge, the evaluations described in Section 5.3.3 of the protocol will be performed to assess 
and document the patient’s readiness to be discharged according to the criteria in Section 5.3.4.  
6 STUDY DRUG AND PHARMACEUTICAL INFORMATION  
6.1 Poziotinib 
Poziotinib will be supplied by Spectrum.  
6.2 Poziotinib Composition 
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet 
for oral administration. 
6.3 Poziotinib Supply and Labeling 
Poziotinib tablets are supplied in 2.0-mg and 8.0-mg dose strengths. 
6.4 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. 


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6.5 Poziotinib Administration 
Poziotinib should be taken with food and a glass of water (approximately 240 mL) at 
approximately the same time(s) each day.  
Once a Day Dosing:  
• Phase 1, Days 1 to 14: Patients will be administered poziotinib every 24 (±1) hours  
• Phase 1 post-Hospitalization and Phase 2: If the daily dose is missed, this dose may be 
administered any time during the day, but at least 8 hours prior to the next scheduled 
dose. 
Twice a Day Dosing:  
• Phase 1, Days 1 to 14: Patients will be administered poziotinib every 12 hours 
(±30 minutes) 
• Phase 1 post-Hospitalization and Phase 2: The first dose should be taken in the 
morning and the second dose should be taken approximately 8 to 12 hours later. If a dose 
is missed, and there is less than 8 hours before the next scheduled dose, the dose should 
be skipped and the next dose taken as scheduled. 
6.6 Diarrhea Management 
Tyrosine kinase inhibitors may cause diarrhea when taken. Prophylaxis for this is strongly 
encouraged and may be addressed by the Investigator using the Institute’s standard of care. Any 
prophylaxis treatment will be recorded in the CRF and the source documents. 
6.7 Poziotinib Dose Modification Recommendations 
In Phase 1 of the study (Dose-Finding), dosing modifications are not allowed during Cycle 1 but 
are allowed beginning with Cycle 2. Dosing modifications are allowed at any time during 
Phase 2 of the study. Dosing modifications are described in Table 3. If needed, doses will be 
reduced by 2 mg/dose (i.e., if on QD, the reduction will be a total of 2 mg/day or if on BID, the 
reduction will be a total of 4 mg/day),  regardless of starting dose, and will be at the 
Investigator’s discretion; the Sponsor should be notified. Dose modifications not described in the 
table below must be discussed with Medical Monitor for approval. After dose reductions, if the 
patient has a documented confirmed progression, the patient’s dose can be increased up to the 
starting dose.  




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7 SAFETY ASSESSMENT 
7.1 Safety Measures 
It is the responsibility of the Principal Investigator to oversee the safety of the patients and to 
report all AEs/SAEs that are observed or reported during the study, regardless of relationship to 
study drug or clinical significance.  
All patients taking study drug will be subject to DLT assessments, but patients in Phase 2 are 
unlikely to have DLTs, given that the dose of drug they are taking, is below the MTD determined 
in Phase 1. 
The investigator together with the Sponsor’s Medical Monitor will review all safety information 
per patient at each dose-finding meeting. 
Safety data will also be reviewed on a regular basis by Spectrum’s study monitoring team, which 
includes a Clinical Research Associate (CRA), Clinical Trial Manager (CTM), 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 5.0 for AE grading. 
7.2 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient, temporally associated with the use of a medicinal product, 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. 


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• 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 and death due to disease progression. 
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.  
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, all SAEs are to 
be recorded. In addition, SAEs that occur after 35 (±5) days after the last dose of study treatment 
where a causal relationship with the study drug is suspected will also be recorded on the AE 
CRF. 
The resolution of all AEs must be routinely recorded and be reconciled 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. 
• 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 CTCAE Grade (Section 7.3.2), relationship to study drug 
(Section 7.5), and as serious or nonserious (Section 7.7) by the Investigator. 




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The most common AEs associated with poziotinib treatment include: 
• Diarrhea 
• Rash 
• Stomatitis 
• Fatigue 
• Vomiting 
• Decreased Appetite  
• Dry Skin 
• Nausea 
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, all SAEs 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 and SAEs that occur 
after 35 (±5) days after the last dose of study treatment where a causal relationship with the study 
drug is suspected are to be reported to Spectrum within 24 hours of knowledge of the event.  
SAEs are to be reported and the serious adverse event report (SAER) faxed or e-mailed within 24 
hours of knowledge of the event to the study Sponsor: 


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Spectrum Pharmaceuticals, Inc. 
Primary Contact: Pharmacovigilance Department  
Fax: + 1 (949) 861-6599 
E-mail: drugsafety@sppirx.com 
Spectrum may request additional information from the Principal 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. 
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 Principal 
Investigator is responsible for submitting SAEs to his/her site’s Institutional Review Board 
(IRB)/Ethics Committee (EC) through the head of the study site. Copies of each SAER, and 
documentation of IRB/EC notification and acknowledgement of receipt, will be kept in the Site’s 
Regulatory Binder. 
In addition, all deaths that occur on study will be reported on a death CRF page.  
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 and death due to disease progression. 
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. 


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Any pregnancy involving a study patient or a patient’s partner that occur from the first dose of 
study treatment through 35 (±5) 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 
pharmacokinetic analysis plan, providing full technical details, will be finalized prior to database 
lock. 
8.1 Sample Size  
The current study will be conducted in 2-parts, and the total sample size is approximately 76 
patients. Phase 1 is a dose-finding study using 3+3 design to determine the MTD/MAD in each 
dosing group (QD or BID). Up to 18 patients (up to 3 dose levels, up to 6 patients each level) 
will be included for DLT evaluation in each dosing group for a total of 36 patients in Phase 1. 
Patients who discontinue from the study before completing Cycle 1 treatment for reasons other 
than DLTs are not qualified for DLT evaluation and will be replaced.  
Once the dose and regimen are identified, patients will be enrolled into Phase 2 to confirm the 
safety and evaluate the preliminary efficacy of poziotinib using the selected dose and schedule. 
In Phase 2, two cohorts of 20 patients each will be enrolled in previously treated NSCLC patients 
with EGFR Exon 20 insertion mutations and HER2 exon 20 insertion mutations respectively. 
Although no a priori test of hypothesis and statistical powering is specified in this study, the 
statistical methods and test of comparison follows that of SPI-POZ-202, a global pivotal study. 
In that study, a single arm hypothesis testing to reject non-desired ORR of 17% vs. clinically 
meaningful ORR of 30% will be evaluated for previously treated NSCLC patients with EGFR 
Exon 20 insertion mutations and HER2 exon 20 insertion mutations respectively.  
The above sample size of 20 patients in each mutation cohort will provide a width for 95% 
confidence interval of 0.424 for the expected ORR of 30%.  
8.2 Method of Treatment Assignment 
Patients in Phase 1 will be randomized. There is no randomization in Phase 2 and patients will be 
enrolled sequentially.  
The study design for Phase 1 combines randomization and dose escalation. Randomization will 
be balanced for every 6 patients and stopped when the MTD/MAD is determined for either the 
QD or BID group. Patient enrollment will be on hold after 6 patients and resume when the next 
dose level is determined for both QD and BID groups. This process will continue for every 
6 patients until MTD/MAD is determined for one of the dosing schemes, and randomization will 
be stopped. Then patient enrollment will resume and be on hold for every 3 patients until the 


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MTD/MAD is determined for the other dosing scheme. Patients who discontinue for reasons 
other than DLTs will be replaced.  
8.3 Analysis Populations 
Two analysis populations have been defined for each cohort as follows: 
• The Evaluable Population consists of all patients in Phase 2 who are enrolled, complete 
at least 1 cycle of poziotinib treatment, and is evaluable for tumor response based on 
RECIST, Version 1.1 criteria. The efficacy data will be analyzed using the Evaluable 
Population.  
• The Safety Analysis Population 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 Safety Analysis 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). Further details of the criteria and conduct of the 
statistical analyses will be included in the SAP for this study. 
Descriptive statistics will be used to describe the recovery of radioactivity and PK parameters. 
Pharmacokinetic parameters will be computed and analyzed by standard analytical methods. 
8.5 Efficacy Analyses 
Phase 1: No efficacy analyses will be performed in Phase 1. 
Phase 2: The primary efficacy variables, as described below, will be summarized and analyzed 
descriptively, along with 95% CI, for each cohort based on local radiographic review. 
• Objective Response Rate (ORR) will be assessed according to the Response Evaluation 
Criteria in Solid Tumors (RECIST) Guidelines, version 1.1 [22] 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 Evaluable Population.  
The primary endpoint analysis will be performed using point estimate and the 95% CI.  
8.5.1 Secondary Endpoints 
• 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.  
• DoR will be measured from the date that measurement criteria are first met for CR or PR 
(whichever status is recorded first) until the first subsequent date that progressive disease 
or death is documented. 
• 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. 


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DCR, DoR, and PFS will be analyzed using descriptive statistics, for each cohort, and with 
95% CI for DCR and Kaplan-Meier plot for DoR and PFS.  
8.5.2 Exploratory Endpoints 
• Overall Survival is defined as the number of days from the treatment start date to the 
date of death due to any cause. After study drug discontinuation, patients who have 
consented will be contacted every 3 months, for up to 2 years after patient’s first dose of 
poziotinib, for survival assessment.  
8.6 Safety Analysis 
Safety analysis will include collection of adverse events, DLTs for determination of MTD/MAD, 
and pharmacokinetics.  
8.6.1 Safety and Adverse Events  
Safety will be assessed by reported/elicited AEs, laboratory assessments including hematology 
and chemistry, 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. 
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 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. 
Serious adverse events reported prior to treatment but after IC will be provided in a listing. 
The number of completed cycles will also be summarized and analyzed descriptively. 
All laboratory abnormalities will be classified according to CTCAE version 5.0 and summarized 
by toxicity grade.  
8.6.2 Pharmacokinetics  
The pharmacokinetics of poziotinib and M1 and M2 metabolites evaluated. The timing for PK 
blood draws will be: 
• Phase 1: All patients will have PK blood samples drawn predose and 30 minutes, 1, 2, 3, 
4, 6, 8, 12, 14, and 24 hours postdose on Cycles 1, Days 1 and 13. In addition, if a patient 
presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, 


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pneumonitis), PK blood samples will be collected as soon as possible following the onset 
of the AE and the time of the last dose and the time of blood draw should be recorded. 
• Phase 2: All patients in Phase 2 will have blood samples drawn predose and at 1 hour 
and 2 hours postdose for sparse PK sampling and time-matched concentration- ECG 
analysis on Cycle 1, Day 1 and Cycle 2, Day 1 for time-matched concentration- ECG 
analysis. Blood samples will also be collected on Cycle 3, Day 1 then every 8 weeks 
thereafter in order correlate poziotinib concentrations with ctDNA and efficacy; the time 
of the last dose and the time of blood draw should be recorded. In addition, if a patient 
presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, 
pneumonitis), blood samples will also be collected as soon as possible following the 
onset of the AE and the time of the last dose and the time of blood draw should be 
recorded. 
9 ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT  
9.1 Investigator and Study Site Responsibilities  
The study will be monitored by employees or representatives of Spectrum. CRAs will monitor 
the site on a periodic basis and perform verification of source documentation for each patient as 
well as other routine compliance reviews. The Sponsor’s Safety Physician and 
Pharmacovigilance Department will review safety data and be responsible for ensuring timely 
reporting of expedited SAERs to regulatory agencies, the head of study site 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, the clinical study protocol, standards stipulated in Article 14, 
Paragraph 3 and Article 80-2 of the “Law on Securing Quality, Efficacy and Safety of Products 
including Pharmaceuticals and Medical Devices (MHLW)”, and “Ministerial Ordinance on Good 
Clinical Practice for Drugs (MHLW)”. 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 head of study site 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 Principal Investigator with an Informed 
Consent template. The Investigator may rearrange or reword the contents of the template, or may 


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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 through the head of the study site. 
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. 
9.1.4 Study Files and Retention of Records 
The head of study site, the Investigator and IRB are to retain all study records until after the last 
approval of a marketing application in Japan or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product or until at least 3 years 
after the early termination or completion of the study whichever comes later as per GCP. 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 head of study site and 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 head of study site 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 date, time, and amount of poziotinib administered to patients. 
The CRA will review inventory and accountability documentation during monitoring visits. 
The Investigator will not supply the investigational study drugs to any other investigators who 
are not contracted to perform the study. Investigational study drug use, other than as directed by 
this protocol, is not allowed. 
All unused bottles 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. Unused poziotinib 


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pills and bottles will be returned to the designated depot and destroyed according to local laws, 
and all applicable policies and procedures.  
The head of study site has a responsibility of the investigational product control/accountability 
within the study site. Accurate records of all Poziotinib supplies received at, dispensed from, 
returned to, and disposed of by the study site should be recorded and preserved by the head of 
study site or the investigational product storage manager. 
After study conclusion, all unused bottles of poziotinib may be returned to the designated depot 
following verification of accountability by a Sponsor 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. 
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 and Safety Physician 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 head of study site and 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, the head of study site 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. 


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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, PMDA in Japan, 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. 


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Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and 
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Robichaux JP, Le X, Elamin YY, Nilsson MB, Hu L, He J, et al. Activity of second-gen 
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Robichaux JP, Elamin YY, Vijayan RSK, Nilsson MB, Hu L, Zhang F, et al. Pan-cancer 
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14. 
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r) 
On Cycle 1, Day 1 and Cycle 1, Day 13, patients will have intensive pharmacokinetic (PK) samples drawn (4 mL whole blood at each time point) predose and 30 minutes, 1 and 2 (±15 minutes) 
postdose, and 3, 4, 6, 8, 12, 14 (±30 minutes) postdose, and 24 hours (±1 hour) postdose. In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, 
diarrhea, pneumonitis), blood samples will be collected as soon as possible following the onset of the AE and the time of the last dose and the time of blood draw should be recorded  
s) 
Poziotinib will be dispensed on Day 1 of each cycle. Poziotinib should be taken with food and a glass of water (approximately 240 mL) at approximately the same time(s) each day.  
t) 
During the Screening Period, only SAEs  will be recorded . All AEs will be collected from Cycle 1, Day 1 through the Safety Follow-up Visit. Patients will be hospitalized during the first 2 weeks of 
the study and will be monitored for safety assessments including AEs, vital signs, ECGs on Day 7 and Day 14 of Cycle 1. Adverse events will be assessed daily while hospitalized. 
u) 
Telephone contact for AE and concomitant medication assessment on Cycle 1, Day 22 (±2 days), weekly during Cycle 2 and then Day 15 (±2 days) in subsequent cycles. During the long-term follow-
up patients will be contacted every 3 months to assess survival.  
 






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s) 
Cardiac ejection fraction will be evaluated using echocardiogram or multi-gated acquisition (MUGA) scan at Screening. The Investigator can order subsequent tests based on patient standard of care.  
t) 
Patients will have blood samples drawn predose and at 1 hour and 2 hours (±15 min) postdose on Cycle 1, Day 1 and Cycle 2, Day 1 for sparse PK sampling and time-matched concentration-ECG 
analysis. Blood samples will be collected at Cycle 3 Day 1 and then every 8 weeks in order correlate poziotinib concentrations with plasma ctDNA and efficacy; the time of the last dose and the time 
of blood draw should be recorded. In addition, if a patient presents with a potentially drug-related Grade ≥3 TEAE (e.g., rash, mucositis, diarrhea, pneumonitis), blood samples will be collected as 
soon as possible following the onset of the AE and the time of the last dose and the time of blood draw should be recorded.  
u) 
Poziotinib will be dispensed on Day 1 of each cycle. Poziotinib should be taken with food and a glass of water (approximately 240 mL) at approximately the same time(s) each day.  
v) 
During the Screening Period, only SAEs  will be recorded . All AEs will be collected from Cycle 1, Day 1 through the Safety Follow-up Visit.  
w) Concomitant medications will be collected at Day 1 of each cycle, Day 8 and Day 15 during Cycle 1, and at the Safety Follow-up Visit. 
x) 
Telephone contact will be made to collect AE and concomitant medication information from patients on Cycle 1, Day 22, every week in Cycle 2, and Day 15 (±2 days) in each cycle thereafter. 
During the long-term follow-up patients will be contacted every 3 months to assess survival.  
 
 
 




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RASH MANAGEMENT RECOMMENDATIONS 
Given the presence of wild type EGFR receptors in the skin, rash is a common, expected toxicity 
of tyrosine kinase inhibitor (TKI) compounds. For rash management, at the treating 
Investigator’s discretion, the following interventions are strongly recommended.  
Early and regular contact with the PI or dermatologist should be arranged for and provided prior 
to initiating dosing. At Baseline, an education session should be provided to the patient to inform 
them of likely skin events while on study and directions given on how to contact the appropriate 
member of the health care team. Visits on Days 8 and 15 should include a focus on skin and 
mucosal assessment. Per protocol, visits or telephone contact should be made with the patient 
every week during Cycles 1 and 2 and then every 2 weeks while being treated with study drug.  
Supportive medications, including early steroid use, should be considered even in the presence of 
low-grade “on-target” toxicity (eg, rash).  
Preliminary information from Cohort 1 suggest that dose interruptions should be minimized in 
order to reduce the risk of progression. 
 
CTCAE Severity Grading of Rash 
Skin and 
subcutaneous 
tissue 
disorders 
GRADE 
Adverse 
Event 
1 
2 
3 
4 
5 
Rash 
Acneiform 
Papules and/or 
pustules covering 
<10% BSA, which 
may or may not be 
associated with 
symptoms of 
pruritus or 
tenderness 
Papules and/or 
pustules covering 
10 - 30% BSA, 
which may or may 
not be associated 
with symptoms of 
pruritus or 
tenderness; 
associated with 
psychosocial 
impact; limiting 
instrumental ADL 
Papules and/or 
pustules covering 
>30% BSA, which 
may or may not be 
associated with 
symptoms of 
pruritus or 
tenderness; limiting 
selfcare ADL; 
associated with local 
superinfection with 
oral antibiotics 
indicated 
Papules and/or pustules 
covering any % BSA, 
which may or may not 
be associated with 
symptoms of pruritus or 
tenderness and are 
associated with 
extensive 
superinfection with IV 
antibiotics indicated; 
life-threatening 
consequences 
Death 
Rash Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and 
back. 
Abbreviations: ADL = activities of daily living; BSA = body surface area;  
 
 
 


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