Clinical trial NCT04172597
Conditions: Breast Cancer Colorectal Cancer Solid Tumor Glioblastome Multiforme
Keywords: EGFR activating mutations HER2 activating mutations HER2-positive breast cancer HER2-negative breast cancer
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2019-12-23; Completion date: 2022-03-29
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, open-label, multicenter study whose principal objectives are to evaluate the efficacy and safety/tolerability of poziotinib in five cohorts of 30 previously-treated patients each.

Detailed description:
The Screening period (Day -30 to Day 1) begins 30 days prior to poziotinib treatment on Day 1 of Cycle 1. Patients must meet all Inclusion/Exclusion Criteria and provide informed written consent prior to study procedures.

The duration of each treatment cycle is 28 days. There will be five patient cohorts. Eligible patients will be enrolled into cohorts concurrently based on EGFR or HER2 exon 20 mutation status.

* Cohort 1: HER2-positive or HER2-negative breast cancer (BC) with a HER2 activating mutation.
* Cohort 2: Colorectal cancer (CRC) with a HER2 activating mutation.
* Cohort 3: Any solid cancer, except non-small cell lung cancer (NSCLC), BC, or CRC with a HER2 activating mutation.
* Cohort 4: Glioblastome multiforma (GBM) with an EGFR activating mutation.
* Cohort 5: Any solid cancer, except NSCLC or GBM with an EGFR activating mutation.

All patients will be treated daily for up to 24 months unless there is disease progression, death, intolerable adverse events (AEs), or another protocol-specified reason for patient withdrawal. After treatment discontinuation, patients will be contacted every 3 months for up to 2 years after the first dose of poziotinib to assess survival.

Arms: arm 1: Patients with HER2-positive or HER2-negative BC with a HER2 activating mutation will receive poziotinib 8 milligrams (mg), orally, twice daily (BID) starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed. arm 2: Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed. arm 3: Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed. arm 4: Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed. arm 5: Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Interventions: intervention 1: Poziotinib Hydrochloride intervention 2: Loperamide
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: Loperamide as prescribed by the physician.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase 2 Study of Poziotinib in Patients with EGFR or HER2 
Activating Mutations in Advanced Malignancies 
NCT Number: 
NCT04172597 
Document Date: 
Protocol Amendment 1: 20 May 2021 
 
 
 


















Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1:   20 May 2021 
Confidential 
1 
 
CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
 
TITLE PAGE 
Study Title:  
A Phase 2 Study of Poziotinib in Patients with EGFR or HER2 
Activating Mutations in Advanced Malignancies 
Study Number:  
SPI-POZ-203  
Study Phase:  
Phase 2  
 
Study Drug:  
Poziotinib 
IND Number:  
140296  
Sponsor:  
Spectrum Pharmaceuticals, Inc. 
Research and Development  
157 Technology Drive 
Irvine, CA  92618 
USA 
Protocol Version/Date:  
Amendment 1 / 20 May 2021 
 
This study is to be conducted according to the applicable US and international standards of Good 
Clinical Practice (US Code of Federal Regulations Title 21 Part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or 
under control of Spectrum Pharmaceuticals, Inc. and is provided to you in confidence as an 
Investigator, potential Investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board/Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Spectrum Pharmaceuticals, Inc. except to the extent necessary to obtain Informed Consent from 
those persons to whom the drug may be administered.


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
2 
INVESTIGATOR SIGNATURE  
Protocol Number: SPI-POZ-203  
A Phase 2 Study of Poziotinib in Patients with EGFR or HER2 Activating Mutations in 
Advanced Malignancies  
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) Guideline for Good Clinical Practice (GCP) as presented adopted by FDA. 
I will provide copies of the protocol and of the clinical and preclinical information on the 
investigational product, which was furnished to me by the Sponsor (Spectrum Pharmaceuticals, 
Inc.), to all members of the study team responsible to me who participate in the study. I will 
discuss this material with them to assure that they are fully informed regarding the study drug 
and the conduct of the study. 
I will perform the study according to specifications outlined in the protocol, applicable laws and 
regulations, and the applicable clinical trial agreement and agree to implement protocol 
requirements only after the protocol and patient information/Informed Consent form have been 
approved by the Institutional Review Board/Ethics Committee (IRB/EC). I will submit any 
protocol modifications (amendments) and/or any Informed Consent form modifications to the 
IRB/EC, and approval will be obtained before any modifications are implemented. 
I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior 
consent from Spectrum Pharmaceuticals, Inc., unless this requirement is superseded by a 
regulatory authority (e.g., FDA) in which case I will follow the procedures for disclosure 
described in the applicable clinical trial agreement. 
 
__________________________________ 
Investigator Name (PLEASE PRINT):  
 
Signature: ________________________________ Date ______________  
  
 
 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
3 
SYNOPSIS  
Title of Study: A Phase 2 Study of Poziotinib in Patients with EGFR or HER2 Activating Mutations in 
Advanced Malignancies 
Name of Sponsor: Spectrum Pharmaceuticals, Inc. 
Name of Investigational Product: Poziotinib 
Study Centers: Approximately 25 study centers 
Planned Number of Patients: Approximately 150 patients (30 patients per cohort) 
Duration of Study: Approximately 4 years, including enrollment and 
follow-up 
Clinical Phase: 2 
Objectives:  
Primary Objective 
• 
To evaluate the Objective Response Rate (ORR) of poziotinib in patients with EGFR or HER2 mutation-
positive malignant solid tumors.  
Secondary Objectives 
• 
To evaluate other efficacy variables of poziotinib in patients with EGFR or HER2 mutation-positive, 
malignant solid tumors, including the following: 
• 
Duration of Response (DoR) 
• 
Disease Control Rate (DCR)  
• 
To evaluate the Safety and Tolerability of poziotinib in patients with EGFR or HER2 mutation-positive 
malignant solid tumors 
Exploratory Objectives 
• 
To evaluate the following additional efficacy outcomes: 
• 
ORR, DCR, and DoR in patients with baseline CNS metastases  
• 
Overall Survival (OS) and Progression-free Survival (PFS) 
• 
Relationship between molecular biomarkers and clinical outcome 
Duration of Study: The total duration of the study will be approximately four (4) years, including enrollment 
and follow-up. The duration of study participation for each patient includes the following:  
• 
Screening Period: Up to 30 days 
• 
Treatment Period: 28 days per cycle for up to 24 months of treatment or until death, intolerable 
adverse events, progressive disease or other protocol-specified reasons for patient withdrawal  
• 
End-of-Treatment Visit: 30 (±5) days after the last dose of poziotinib  
• 
Long-Term Follow-up: After treatment period 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.  
Patient Replacement Strategy: Patients not efficacy evaluable i.e. not completed at least 1 cycle of poziotinib 
treatment and have baseline and at least 1 post-baseline tumor response evaluation using RECIST, version 1.1 
(and/or RANO for Cohort 4) will be replaced unless they have discontinued from treatment or from the study 
due to disease progression or probable disease progression (eg. clinical progression, initiation of new therapy) or 
due to toxicity. 
Study Design and Methodology 
This is a Phase 2 multicenter, open-label study to evaluate the efficacy and safety of poziotinib in patients with 
EGFR or HER2 mutation-positive malignant solid tumors.  


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
4 
The study is a basket trial with five cohorts. The primary analysis will be conducted for each cohort separately. 
The five cohorts are:  
• 
Cohort 1: Patients that have HER2-positive or HER2-negative, breast cancer with HER2 activating 
mutations (see Table A) (N=30) (See Inclusion Criteria #4) 
• 
Cohort 2: Patients that have colorectal cancer with HER2 activating mutations (see Table A) (N=30) 
• 
Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with 
HER2 activating mutations (see Table A) (N=30) 
• 
Cohort 4: Patients that have GBM with EGFR activating mutations (see Table A) (N=30) 
• 
Cohort 5: Patients that have solid tumors (except NSCLC or GBM) with EGFR activating mutations 
(see Table A) (N=30) 
This study includes a two-stage design in each cohort separately. The first-stage of each cohort will enroll 9 
patients. Details of the two-stage design are provided in the statistical section. A cohort will enroll patients into 
the second-stage if the required responses are observed in 9 patients in the first-stage for each cohort. 
Dosing Regimen 
The starting dose of poziotinib is 8 mg, twice per day (BID). Poziotinib will be self-administered by the patient 
orally, with food and a glass of water, at approximately the same time(s) each day during each 28-day cycle. 
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, it should be taken once remembered or with the next dose if on the same day. 
All patients will be given loperamide for daily use, starting from the first day of the study (4 mg two to three 
times a day or according to the treating physician’s instruction). Poziotinib dose modifications are allowed based 
on the guidelines provided (Table 2). 
The Screening period (Day -30 to Day 1) lasts up to 30 days prior to Cycle 1, Day 1. Patients must provide 
written Informed Consent prior to undergoing any study procedure. Patients must meet all Inclusion/Exclusion 
Criteria in order to participate in the study. Each treatment cycle is 28 calendar days in duration, regardless of 
dosing interruptions. Tumor assessments are scheduled at Baseline/pre-dose, Week 4, Week 8 and every 8 weeks 
thereafter. In the event of a response (PR or CR), a confirmatory scan may be performed 4 weeks from the initial 
response. Pre-dose tumor assessments must be within 14 days prior to Cycle 1, Day 1 (Baseline assessments may 
be used if obtained within 14 days prior to Cycle 1, Day 1). 
The treatment period for all patients will be from the time of the first dose of poziotinib to the first occurrence of 
disease progression, intolerable adverse events, the start of a new anti-cancer treatment, withdrawal of consent or 
death.  
Following radiologic disease progression, the patient may continue to receive poziotinib in an Extension Study 
(SPI-POZ-501) only if the following criteria are met: absence of signs and symptoms indicating clinical 
deterioration due to progression of disease or drug toxicity and absence of decline in ECOG performance status, 
or the investigator and medical monitor agree that the patient continues to derive clinical benefit despite 
progressive disease.  
SPI-POZ-501 Extension Study 
Patients who wish to participate in the extension study must provide written Informed Consent. Treatment will 
begin after the patient has completed the End-of-Treatment (EOT) Visit in the Original Study (ie visit in SPI-
POZ-203 study). Assessments obtained at the EOT visit in the Original Study will serve as Baseline data for the 
extension study.  
Patients will continue to receive poziotinib at the last dose level and schedule received in the POZ-203 study. 
Poziotinib dose modifications will be allowed under the treating physician’s discretion after consultation and 
approval from the Spectrum medical monitor.  
Safety will continue to be followed during the extended treatment according to Standard of Care (SOC). Efficacy 
of continued poziotinib treatment will be evaluated by imaging according to the Institution’s SOC, but at least 
every 2 cycles.  
A patient may continue to receive poziotinib treatment as long as the patient is deriving clinical benefit, as judged 
by consensus of the investigator and Spectrum medical monitor, or until withdrawal of consent, unacceptable 
toxicity, the patient is lost to follow-up, poziotinib receives commercial approval in their country of residence, or 




Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
6 
Extracellular & 
Transmembrane 
EGFRvIII, R108K, R222C, A289T, P596L, G598V 
Kinase Domain 
Exon 20 insertion, E709X, E709_T710del insD, 
L718X, G719X, I740_K745dupIPVAIK, 
I740_K745dup, V742I, L747X, E746_A750del, 
A750P, S768I, S768I/V769L, S768I/V774M, L833V, 
V769M, V774M, R831C, R831H, L858R, L861Q, 
A864V 
7. Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, 
version 1.1) and/or RANO Criteria for Cohort 4. Target lesion(s) must be radiographically measurable. 
CNS metastatic lesions cannot be considered target lesions in Cohorts 1-3 and in Cohort 5. 
8. Brain metastases may be allowed if the patient’s condition is stable. Stable condition is defined as 
having stable neurological symptoms, with no requirement for anti-seizure medications or >2 mg/day 
dexamethasone equivalent or increasing doses of systemic corticosteroids (except Cohort 4 where anti-
seizure medication [Keppra] and dexamethasone up to or equivalent to 4 mg daily is allowed), and no 
evidence of CNS disease progression documented for at least 4 weeks after CNS-directed treatment (eg. 
whole brain radiation), as ascertained by clinical examination and brain imaging (MRI or CT) during the 
screening period. Patients must complete CNS-directed treatment and return to stable condition prior to 
eligibility assessment for the study. For patients who have had radiation therapy, post-treatment MRI 
tests should show no increase in brain lesion size/volume and no new lesions compared to pre-treatment 
MRI (except Cohort 4) for at least 4 weeks. A new lesion is defined as lesion size greater than 5 mm 
and not previously present. 
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.  
10. Patient has recovered from prior systemic therapy for advanced or 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:  
• 
Absolute neutrophil count (ANC) ≥1.0×109/L  
• 
Platelet count ≥75×109/L 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤1.5×ULN; if hepatic metastases are present, ≤2.0×ULN  
• 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine 
aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤2.5×upper limit of normal 
(ULN); if hepatic metastases are present, ≤5.0×ULN 
• 
Creatinine Clearance 
• 
Creatinine clearance ≥ 50 mL/min (calculated according to Cockcroft and Gault 
formula: CCr = {((l 40–age) x weight)/(72xSCr)}) x 0.85 (if female), Scr in mg/dL) 
or  
• 
GFR >= 45 ml/min/1.73m2 as calculated by the CKD-EPI Creatinine Equation (2009) 
(https://www.kidney.org/professionals/kdoqi/gfr_calculator)  
11. Patient with childbearing potential is willing to practice 2 forms of contraception, one of which must be 
a barrier method, from study entry until at least 30 days after the last dose of poziotinib.  
12. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to 
study treatment. Females who are postmenopausal do not require this test (Postmenopausal is defined as 
any of:  age >60 years, age <60 years and amenorrheic for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) 
and estradiol in the postmenopausal range, or prior bilateral oophorectomy, or if taking tamoxifen or 
toremifene, or age <60 years with FSH and plasma estradiol in postmenopausal ranges).  
Exclusion Criteria:   


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
7 
1. Patient has primary tumors in central nervous system (CNS), meningeal carcinomatosis, leptomeningeal 
carcinomatosis, spinal cord compression, or unstable brain metastasis except if qualified under inclusion 
criteria for Cohort 4.  
2. Patients with the T790M mutation in EGFR.  
3. Patients with breast or gastric cancers without eligible HER2 mutations (see Table A).  
4. Patient has received anticancer chemotherapy, biologics, immunotherapy, targeted therapy (including 
HER2 targeted therapy), curative-intent radiotherapy, or other investigational treatment within 15 days 
of study entry. Palliative local radiation therapy for bone metastasis may be allowed. Standard and 
approved hormonal therapies for hormonal receptor positive tumors are allowed. For Cohort 4, patients 
who have prior single agent VEGF inhibitor therapy (eg bevacizumab) are excluded. 
5. Patient has used or will continue to use strong inhibitors/inducers of CYP3A4 and CYP2D6 within 2 
weeks prior to or during the study. 
6. Patient has not recovered (i.e, > Grade 1) from drug-induced pancreatitis or has a history of drug-
induced pancreatitis. 
7. Patient has interstitial lung disease (ILD) or history of ILD or pneumonitis or is less than 30 days from 
last dose of CPI. 
8. Patient has ≥ Grade 2 skin disorders (rash), mucositis, or stomatitis within previous 15 days.  
9. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart 
Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment. 
10. Patient has a high risk of cardiac disease, as determined by the Investigator. If patient is deemed to have 
a high cardiac risk, enrollment may be considered if echocardiogram (ECHO) or multi-gated acquisition 
(MUGA) during Screening demonstrates a cardiac ejection fraction >50%. 
11. Patient has a QTc > 470 ms. 
12. Patient has a history of other malignancies within the last 1 year, except for non-melanoma skin cancer, 
carcinoma in situ of the cervix, or PSA-stable, asymptomatic early stage prostate cancer or superficial 
bladder cancer without active treatment.  
13. Patient has clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or 
coloenteritis as the main symptom (i.e. acute enteritis, malabsorption, or Common Terminology Criteria 
for Adverse Events (CTCAE, version 5.0) Grade 2 or higher diarrhea due to other drug-related reasons 
within 15 days. 
14. Patient is unable to take drugs orally due to disorders that may affect gastrointestinal function or has 
malabsorption syndrome. 
15. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic 
biliary stones, liver metastasis, or stabilized chronic liver disease).  
16. Patient has a medical condition that in the opinion of the investigator or medical monitor would put 
her/him at an unreasonable risk during the trial  
17. Patient has known hypersensitivity to poziotinib or history of allergic reactions attributed to a compound 
of similar chemical composition to poziotinib.  
18. Patient has an active or uncontrolled infection, active bleeding disorder, any underlying medical 
condition, or other serious illness that would impair the ability of the patient to receive protocol 
treatment. 
19. Patient has had recent major surgery or invasive procedure within 15 days prior to starting study 
treatment. 
20. Patient is pregnant or breast-feeding. 
Investigational Product, Dose, and Route of Administration:  
Poziotinib is supplied as 8-mg tablets and 2-mg tablets. The starting dose of poziotinib is 8 mg, twice per a day 
(BID). Patients will self-administer poziotinib orally with food and a glass of water, at approximately the same 
times each day (recorded in a diary). The first dose should be taken in the morning and the second dose should 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
8 
be taken approximately 8 to 12 hours later. If a dose is missed, it should be taken once remembered or with the 
next dose if on the same day.  
Poziotinib Dose Modification will be permitted according to the dose modification guidelines (Synopsis 
Table 2). 
Efficacy Assessments: 
Efficacy will be based on the local radiology evaluation according to RECIST 1.1 (and/or RANO Criteria for 
Cohort 4 as applicable). 
Primary Endpoint:  
• 
Objective Response Rate (ORR) - the rate of confirmed complete response + partial response  
Secondary Endpoints: 
• 
Duration of Response (DoR) 
• 
Disease Control Rate (DCR)  
• 
Safety and tolerability 
Exploratory Endpoints: 
• 
ORR and DoR in patients with baseline CNS metastases   
• 
Overall Survival (OS) and Progression-free Survival (PFS) 
• 
Relationship between molecular biomarkers and clinical outcome  
Pharmacokinetic Assessments: At select study centers, up to 25 patients may be specifically consented for 
intensive PK sampling and concurrent ECGs as defined below:  
Schedule:  Intensive PK blood sampling will be at pre-dose and 2, 4, 8, 12, and 24 hours post-dose on Cycle 1, 
Day 1 and on Cycle 1, Day 8 (±3 days). The 12-hour and 24-hour PK samples must be collected prior to the 
second daily dose. A local 12-lead ECG will be obtained just before each PK blood sample on both Day 1 and 
Day 8. 
If the patient has interrupted continuous poziotinib dosing, clear dosing documentation must be done in order to 
assess suitability of further PK sampling and ECG recording. 
In addition, if a patient presents with a potentially drug-related Grade ≥3 AE, a PK sample should be collected as 
soon as possible, if feasible, following the onset of the AE in order to characterize the PK. Documentation of last 
dose timing prior to the event is required. 
Safety Assessments: 
Safety will be assessed by reported/elicited adverse events (AEs), laboratory assessments including hematology 
and biochemistry, vital signs, physical examination, and neurological examination. The assessment of treatment-
emergent AEs (TEAEs) includes SAEs, AEs leading to study drug discontinuation, and AEs related to the study 
drug. 
Adverse Event and Serious Adverse Event Reporting: 
Adverse events will be recorded from the first dose of study drug administration until 30 (±5) days after the last 
dose of study drug is administered. From the time Informed Consent is signed to the first dose of study drug 
administration, only serious adverse events (SAEs) will be recorded and reported. 


Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
9 
Statistical Methods: 
Sample Size: 
The statistical analysis of each cohort will be performed separately. A total of 30 patients in each cohort will be 
enrolled using Simon’s two-stage design. The optimal two-stage design to test the null hypothesis that p≤0.050 
versus the alternative that p≥0.250 has an expected sample size of 16.76 and a probability of early termination of 
0.630. If the drug is not effective, there is a 0.049 probability of concluding that it is (the target for this value 
was 0.050). If the drug is effective, there is a 0.098 probability of concluding that it is not (the target for this 
value was 0.100). For each cohort, 9 patients will be evaluated in the first stage; the cohort will be terminated if 
0 respond. If the cohort goes on to the second stage, a total of 30 patients will be studied. If the total number 
responding is less than or equal to 3, the cohort is closed. 
Efficacy Analysis: 
The primary efficacy variable ORR is the proportion of patients with confirmed Complete Response (CR) and 
Partial Response (PR) recorded from the start of the first dose of poziotinib to the end of study and will be 
analyzed descriptively along with the 95% CI for each cohort. The determination of ORR will be based upon an 
assessment of the local radiological review by the respective Principal Investigator using RECIST version 1.1 
and/or RANO Criteria (for GBM).  
The secondary endpoints are DCR and DoR, DCR is the proportion of patients with best response of CR, PR, 
and Stable Disease (SD) from the first dose of poziotinib to the end of study; and DoR is the time 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.  
Exploratory endpoints are OS and PFS. OS is the time from the treatment start date to the date of death during 
the study; and PFS is the time from the treatment start date to the date of documented disease progression or 
death during the study.  
DCR, DoR, OS and PFS will be analyzed using descriptive statistics, for each cohort, and with 95% CI for DCR 
and Kaplan-Meier plot for DoR, OS and PFS.  
Analysis Populations: 
The following analysis populations will be defined. 
• 
The Evaluable Population (EP) consists of all enrolled patients who,  completed at least 1 cycle of 
poziotinib treatment, and have baseline and at least 1 post-baseline tumor response evaluation using 
RECIST, version 1.1 (and/or RANO for Cohort 4) or progressed prior to any post-baseline image 
evaluation. All efficacy analyses will be done using the Evaluable Population. 
• 
The Safety Analysis Population (SAF) includes all enrolled patients who received at least 1 dose of 
poziotinib. All demographics, Baseline characteristics, and safety data will be analyzed using the SAF 
population. 
Safety and Tolerability:  
The following variables will be summarized and analyzed descriptively for each cohort: number of completed 
cycles, relative dose intensity, number and percentages of patients with TEAEs, SAEs, TEAEs leading to study 
drug discontinuation, TEAEs related to the study drug; and the severity of TEAEs based on CTCAE, Version 
5.0. 
Protocol Version/Date: Amendment 1/ 20 May 2021 
 
 
 
 






Spectrum Pharmaceuticals, Inc. 
Clinical Study Protocol 
Poziotinib 
Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
Confidential 
12 
f) 
The Screening tumor assessment for patient eligibility will be based on scans performed within 30 days before the patient signed the ICF. Either CT, PET/CT, or MRI scans should be performed for 
non-brain organs and brain MRI scans should be performed locally per standard of care before the patient signed the ICF. Baseline tumor assessment (CT, PET/CT or MRI for non-brain and brain 
MRI) will be performed within 14 days prior to Cycle 1, Day 1 and additional assessments will be made at 4 weeks (Cycle 2, Day 1 [up to Cycle 2, Day 7]), at 8 weeks (Cycle 3, Day 1 [up to Cycle 
3, Day 7, with at least 28 days from previous tumor assessment]), and then every 8 weeks (±7 days) thereafter until disease progression, death, intolerable adverse events (AEs), or other protocol-
specified reasons for patient withdrawal. 
g) 
Tumor histopathology report (from local pathologist) and molecular test report for mutation diagnosis. 
h) 
Complete blood count (CBC), including white blood cells with 5-part differential, hemoglobin, and platelets, is to be obtained within 7 days prior to poziotinib administration on Day 1 of each cycle, 
at which time, the patient’s absolute neutrophil count ≥1.0×109/L and platelet count ≥75 ×109/L before administering the next dose of poziotinib. In addition, a CBC is to be performed on Day 8 of 
Cycles 1 and 2. 
i) 
Blood for chemistry is to be collected within 7 days prior to poziotinib administration on Day 1 of each Cycle. 
j) 
ECGs will be performed at screening. At select study centers, up to 25 patients may be specifically consented for ECG as defined below:  
Schedule:  A local 12-lead ECG will be obtained just before each PK blood sample on both Day 1 and Day 8. If the patient has interrupted continuous poziotinib dosing, clear 
dosing documentation must be done in order to assess suitability of further PK sampling and ECG recording.  
k) 
Cardiac ejection fraction may be evaluated at Screening in patients who are considered at high risk of cardiac disease, as determined by the Investigator, using echocardiogram or multi-gated 
acquisition (MUGA) scan. The investigator can order subsequent tests based on patient standard of care as determined by the Investigator.  
l) 
Tumor genotyping report from local lab is required to confirm patient mutation eligibility. Tissue sample (archival or fresh biopsy), if available, should be retained for retrospective analysis by 
FoundationOne CDx test. Collecting a tissue sample at progression is optional but is highly encouraged.  
m) Plasma samples will be required at Screening and optional on the day of each on-study imaging session, beginning at the 4-week imaging session, once every 8 weeks with imaging scan and when 
the patient progresses for biomarker analysis. Guardant’s 360 or FoundationACT assays will be used, Plasma sample collection and storage will follow vendors’ standard procedures as described in 
the vendors’ Laboratory Manual. 
n) 
Whole blood samples will be drawn at Screening for pharmacogenomic analysis.  
o) At select study centers, up to 25 patients may be specifically consented for intensive PK sampling as defined below:  
Schedule:  Intensive PK blood sampling will be at pre-dose and 2, 4, 8, 12, and 24 hours post-dose on Cycle 1, Day 1 and on Cycle 1, Day 8 (±3 days). The 12-hour and 24-hour 
PK samples must be collected prior to the second daily dose. If the patient has interrupted continuous poziotinib dosing, clear dosing documentation must be done in order to 
assess suitability of further PK sampling and ECG recording. In addition, if a patient presents with a potentially drug-related Grade ≥3 AE, a PK sample should be collected as 
soon as possible, if feasible, following the onset of the AE in order to characterize the PK. Documentation of last dose timing prior to the event is required.  
p) 
Poziotinib and loperamide will be dispensed on Day 1 of each cycle. Patients will take poziotinib orally twice daily with food and a glass of water at approximately the same times each day. 
Loperamide will be given prophylactically for diarrhea as follows: 4 mg twice daily (bid) to three times daily (tid or according to treating physician’s instruction.  
q) 
Adverse events will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) and during Screening only study-related SAEs to be 
recorded. 
r) 
Weekly calls to patients will be conducted during the Days 3 to 8 of each cycle for the first 2 cycles as a follow up of expected adverse events.  
s) 
Patients who have consented will be contacted by phone (or email or letter if specifically requested) every 3 months, for up to 2 years after patient’s first dose of poziotinib, for survival assessment. 
 




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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
INVESTIGATOR SIGNATURE ..................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................14 
List of Tables ..........................................................................................................................16 
List of Figures .........................................................................................................................16 
LIST OF ABBREVIATIONS .....................................................................................................18 
1 
INTRODUCTION ................................................................................................................21 
1.1 
Background ................................................................................................................21 
1.1.1 
Human Epidermal Growth Factor Receptor Family and Cancer ................21 
1.1.2 
Poziotinib ............................................................................................................23 
1.2 
Rationale for the Current Study ...............................................................................35 
2 
STUDY OBJECTIVES ........................................................................................................36 
2.1 
Primary Objective ......................................................................................................36 
2.2 
Secondary Objectives.................................................................................................36 
2.3 
Exploratory Objectives ..............................................................................................36 
3 
INVESTIGATIONAL PLAN ..............................................................................................36 
3.1 
Study Design and Treatment Plan............................................................................36 
3.2 
Study and Treatment Duration ................................................................................38 
4 
PATIENT POPULATION ...................................................................................................38 
4.1 
Inclusion Criteria: ......................................................................................................39 
4.2 
Exclusion Criteria: .....................................................................................................41 
4.3 
Patient Discontinuation/Withdrawal Criteria .........................................................42 
5 
STUDY PROCEDURES ......................................................................................................43 
5.1 
Screening .....................................................................................................................43 
5.2 
Patient Assignment ....................................................................................................43 
5.3 
Timing of Assessments and Procedures ...................................................................44 
5.3.1 
Screening Visit (Within 30 Days of Cycle 1, Day 1) .......................................44 
5.3.2 
Treatment Period – Cycle 1, Day 1 ..................................................................44 
5.3.3 
Treatment Period – Cycle 1, Days 8 and 15 (±3 Days) ...................................45 
5.3.4 
Treatment Period – Cycle 1, Day 22 (±2 Days) (By Telephone) ....................45 
5.3.5 
Treatment Period – Cycle 2, Day 1 ..................................................................45 
5.3.6 
Treatment Period – Cycle 2, Day 8 (±1 Day) ..................................................46 
5.3.7 
Treatment Period – Cycle 3+, Day 1 ................................................................46 
5.3.8 
End-of-Treatment Visit (30 [±5] Days After Last Dose of Study Treatment)
 ...........................................................................................................................46 
5.3.9 
Long-Term Follow-up – Every 3 Months ........................................................47 
5.4 
Description of Study Assessment Parameters .........................................................47 
5.4.1 
Relevant Medical History .................................................................................47 


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5.4.2 
Physical Examination ........................................................................................47 
5.4.3 
Vital Signs ...........................................................................................................47 
5.4.4 
ECOG Performance Status ..............................................................................48 
5.4.5 
Clinical Laboratory Tests .................................................................................48 
5.4.6 
PK Sample ..........................................................................................................48 
5.4.7 
Electrocardiogram (ECG) ................................................................................49 
5.4.8 
Cardiac Ejection Fraction ................................................................................49 
5.4.9 
Tumor Assessment .............................................................................................49 
5.4.10 
Tissue, Plasma, and Whole Blood Samples Retained .....................................50 
5.4.11 
Concomitant Medications .................................................................................50 
6 
STUDY DRUG AND PHARMACEUTICAL INFORMATION .....................................52 
6.1 
Poziotinib ....................................................................................................................52 
6.1.1 
Poziotinib Composition and Formulations .....................................................52 
6.1.2 
Poziotinib Administration .................................................................................53 
6.1.3 
Poziotinib Storage and Handling .....................................................................53 
6.1.4 
Poziotinib Dose Modification Recommendations ...........................................53 
6.2 
Comparator Treatment .............................................................................................54 
7 
SAFETY ASSESSMENT .....................................................................................................54 
7.1 
Safety Measures .........................................................................................................54 
7.2 
Adverse Events ...........................................................................................................54 
7.3 
Guidelines for Recording and Attribution Scoring of Adverse Events ................55 
7.3.1 
Recording of Adverse Events ...........................................................................55 
7.3.2 
Grading of Adverse Events ...............................................................................56 
7.4 
Follow-up of Adverse Events ....................................................................................56 
7.5 
Relationship ................................................................................................................56 
7.6 
Expectedness ...............................................................................................................57 
7.7 
Serious Adverse Events .............................................................................................57 
7.7.1 
Serious Adverse Event Reporting ....................................................................58 
7.7.2 
Exclusions to Serious Adverse Event Reporting Requirements ....................58 
7.8 
Reproductive Risks ....................................................................................................59 
8 
STATISTICAL PLAN..........................................................................................................59 
8.1 
Sample Size .................................................................................................................59 
8.2 
Method of Treatment Assignment ............................................................................59 
8.3 
Analysis Populations ..................................................................................................59 
8.4 
General Statistical Methods ......................................................................................60 
8.5 
Efficacy Analysis: .......................................................................................................60 
8.6
Safety and Tolerability .............................................................................................60 
8.7
Clinical Laboratory Evaluations .............................................................................60 
9 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT ........................61 
9.1 
Investigator Responsibilities .....................................................................................61 
9.1.1 
Good Clinical Practice ......................................................................................61 
9.1.2 
Institutional Review Board/Ethics Committee Approval ..............................61 
9.1.3 
Informed Consent ..............................................................................................61 


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9.1.4 
Study Files and Retention of Records ..............................................................62 
9.2 
Recording and Collecting of Data ............................................................................62 
9.2.1 
Case Report Forms ............................................................................................62 
9.2.2 
Drug Accountability ..........................................................................................62 
9.3 
Protocol Compliance ..................................................................................................62 
9.4 
Sponsor Responsibilities ............................................................................................63 
9.4.1 
Safety Monitoring ..............................................................................................63 
9.5 
Joint Investigator/Sponsor Responsibilities ............................................................63 
9.5.1 
Access to Information for Monitoring and Auditing .....................................63 
9.5.2 
Termination of the Study ..................................................................................63 
9.5.3 
Publication Policy ..............................................................................................63 
9.6 
Confidentiality ............................................................................................................64 
10 REFERENCES .....................................................................................................................65 
     SCHEDULE OF ASSESSMENTS AND PROCEDURES...........................67 
 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS SCALE ..................................................................................................................69 
 
DIARRHEA MANAGEMENT ......................................................................70 
 
RASH MANAGEMENT RECOMMENDATIONS ....................................72 
 
PARONYCHIA MANAGEMENT RECOMMENDATIONS ....................74 
 
List of Tables 
Table 1 
Examples of Important Clinical Inhibitors/Inducers/Substrates for P450 
Enzymes Involved in the Metabolism of Poziotinib...............................................51 
Table 2 
Poziotinib Dose Modifications Recommendations .................................................53 
Table 3 
Investigator Assessment of Adverse Event Causality ............................................56 
 List of Figures 
Figure 1 
EGFR Mutant Cancers ............................................................................................22 
Figure 2 
HER2 Mutant Cancers .............................................................................................23 
Figure 3 
IL-3-Independent Survival of Ba/F3 Cells Stably Expressing EGFR Exon 20 
Mutations ...................................................................................................................24 
Figure 4 
Effect of Poziotinib (HM781-36B) on EGFR Phosphorylation and Downstream 
Signaling ....................................................................................................................25 
Figure 5 
Tumor Volume Change in Mice with EGFR Exon 20 Insertion Mutations 
Treated with Poziotinib Vs. Vehicle ........................................................................25 
Figure 6 
Dose-Response Curves of the Cell Viability of HER2 Mutant A775insYVMA 
Ba/F3 Cells After TKI Treatment for 72 Hours ....................................................26 
Figure 7 
Poziotinib as a Potent Inhibitor for HER2 Mutations in Vitro .............................26 
Figure 8 
Human Breast and Colorectal Cell lines with HER2 Mutations Highly Sensitive 
to Poziotinib in Vitro and in Vivo.............................................................................27 
Figure 9 
Effect of Poziotinib (HM781-36B) on HER2 Phosphorylation and Downstream 
Signaling ....................................................................................................................28 


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Figure 10 MRI Results after Poziotinib Treatment ................................................................29 
Figure 11 Poziotinib efficacy in patients with EGFR exon 20 mutant NSCLC ...................31 
Figure 12  NSCLC Patient with HER2 exon 20 (Y772dupYVMA) mutation ......................32 
Figure 13 CT of Abdomen, May 2017 ......................................................................................33 
Figure 14 CT of Abdomen, August 2017 ..................................................................................33 
Figure 15 PET Scans of the Patient At 1 Day Before and 4 Weeks After Poziotinib 
Treatment ..................................................................................................................34 
Figure 16  Safety Comparison of 16 mg QD vs 8 mg BID ......................................................35 
Figure 17  Diagram of Study Design ........................................................................................38 








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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]. 
Many solid tumors, including lung, breast, bladder, head and neck, and other gastrointestinal 
cancers, are associated with either an activating mutation in or an overexpression of members of 
the ErbB receptor family, especially EGFR and HER2 [2]. EGFR and HER2 mutations, 
including exon 20 insertion mutations, have been identified in a variety of cancer types. 
Treatments that specifically target HER2 overexpression have been shown to be clinically 
beneficial to breast cancer patients and several targeted therapies have been approved by the 
FDA for treatment patients with NSCLC and breast cancer. Similarly, there are investigations of 
FDA-approved EGFR targeting agents in HER2 overexpressed and mutant colorectal, head and 
neck, and pancreatic cancers. In a recent basket trial of patients with lung, breast, bladder, 
colorectal, and several other solid tumors, HER2 mutations were shown to be clinically 
targetable with neratinib; although, outcomes were modest [3]. However, to date, excluding 
NSCLC, there are no FDA-approved targeted therapies for EGFR or HER2 mutant solid tumors. 
The results of nonclinical in vitro and in vivo studies show sensitivity of both EGFR and HER2 
exon 20 mutations across tumor types to poziotinib, a novel oral, irreversible pan-HER inhibitor 
[4]. Clinical efficacy and safety data obtained to date indicate that poziotinib may be beneficial 
to patients with pretreated metastatic lung cancers that harbor these mutations [5, 6]. In addition, 
Spectrum has two compassionate therapy cases with one patient who received poziotinib for 
treatment of lung cancer with a HER 2, exon 19 mutation and in one patient with breast cancer 
with a HER2, exon 20 mutation (Case Reports).  
1.1.1.1 EGFR Mutations in Various Malignancies and EGFR Mutational Hotspots by 
Cancer Type 
Zehir et al. utilized a large-scale, prospective clinical sequencing, comprehensive assay, MSK-
IMPACT, and compiled matched tumor and normal tissue sequence data from a unique cohort of 
more than 10,000 patients with advanced cancer [7]. Using these data, they identified EGFR 
clinically relevant somatic mutations most frequently in non-small cell lung cancer (NSCLC), 
glioma, head and neck carcinoma, stomach, esophagogastric carcinoma and breast (Figure 1). 
Priestley et al. had further defined the EGFR activating alternations in metastatic solid tumors by 
analyzing data from TCGA and ICGC, 2,520 whole genome-sequenced tumor-normal pairs. 
They have reported that EGFR mutations occurred most frequently in cancers of the lung 
(14.5%), stomach (6.9%), esophagus (5.2%), head and neck (4.8%), liver (3%), breast (1.3%) 
and urinary tract (1.2%). EGFR activating mutations occurred most frequently in the exon 19, in 
frame deletion, and in the exon 20, codon L858, followed by exon 20 insertion/duplication 


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mutations, and mutations in codons G719, S768, L861 [8]. Currently, there are FDA-approved 
targeted therapies for EGFR mutant NSCLC with exon 19 deletion and L858R substitution in 
exon 21 (Afatinib, Erlotinib, and Gefitinib), but there is no FDA-approved targeted therapy for 
other solid tumor types.  
Figure 1 EGFR Mutant Cancers 
 
Overview of the MSK-IMPACT cohort. Recurrent somatic alterations across common tumor types. Genes with a cohort-level 
alteration frequency of ≥5% or a tumor type-specific alteration frequency of ≥30% are displayed. Bars indicate the percent of 
cases within each tumor type harboring different classes of genomic alterations. 
1.1.1.2 HER2 Mutations Occur in Various Malignancies, and HER2 Mutational Hotspots 
Vary by Cancer Type. 
Across four public and proprietary databases, HER2 mutations were analyzed within 26 different 
cancer types. HER2 mutations occurred most frequently in bladder, stomach, and bile duct 
cancers (unpublished manuscript); and HER2 exon 20 mutations occurred most frequently in 
cancers of the peritoneal, small intestine, and lung (Figure 2). Across all cancer types, HER2 
mutations occurred most frequently in the extra-cellular domain, followed by exon 20, exon 19, 
and exon 21 (unpublished manuscript). Mutational hotspots varied by malignancy type. These 
hotspot mutations have been tested in vitro, and have demonstrated as activating mutations [5] 
and (unpublished manuscript). A recent basket trial of neratinib enrolled 125 patients with HER2 
mutations, 102 patients with hotspot mutations, and remaining patients with potentially 
oncogenic mutations determined by OncoKB, a curated knowledge database ([3]). Enrolled 
patients had lung, breast, bladder, colorectal, biliary, endometrial, and other solid tumors. The 
study has demonstrated that HER2 mutations are clinically targetable; however, the outcomes 


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with neratinib were modest. Currently, there are no FDA-approved targeted therapies for HER2 
mutant solid tumors. However, there are two on-going Phase 2 clinical trials of poziotinib for 
patients with metastatic NSCLC harboring an exon 20 insertion mutation in either EGFR or 
HER2 (NCT03318939 and NCT03066206).  
Figure 2 HER2 Mutant Cancers  
 
 
HER2 mutations occur in a variety of cancer types with mutational hotspots occurring across the receptor. Bar plot of weighted 
averages of HER2 exon 20 mutation frequency by cancer. Bars are representative of the weighted average ± SEM. Dot sizes are 
representative of the number of patients in each database. (N=390,000). [6] 
1.1.2 Poziotinib 
1.1.2.1 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 a salt form), 
respectively. 
1.1.2.2 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]. 


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1.1.2.3 Nonclinical Data 
1.1.2.3.1 Poziotinib in Tumor Models with EGFR Exon 20 Insertion Mutations 
Poziotinib is active in vitro against cell lines with a range of EGFR exon 20 mutations when 
using the standard Ba/F3 model. Ba/F3 is an interleukin (IL)-3 dependent pro-B cell line that has 
been widely used to study the oncogenic activity of genes and development of drugs that target 
oncogenic drivers. This system was used to test several EGFR exon 20 insertion mutations for 
their effects on IL-3-independent cell survival, signaling, and drug responsiveness [5]. Stable 
expression of EGFR exon 20 insertion mutations rendered Ba/F3 cells IL-3 independent, 
suggesting that these mutations are activating [5]. 
Ba/F3 cells with EGFR exon 20 insertions were then treated with poziotinib. Ba/F3 expressing 
EGFR exon 20 insertions showed marked sensitivity to poziotinib (Figure 3).  
Figure 3 IL-3-Independent Survival of Ba/F3 Cells Stably Expressing EGFR Exon 20 
Mutations 
 
Moreover, poziotinib led to the suppression of EGFR phosphorylation and decreased 
downstream signaling, that was associated with an increased level of cleaved PARP suggesting 
that treatment with poziotinib leads to cell apoptosis (Figure 4) [9]. 


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Figure 4 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 5) [9]. 
Figure 5 Tumor Volume Change in Mice with EGFR Exon 20 Insertion Mutations 
Treated with Poziotinib Vs. Vehicle 
 
1.1.2.4 Poziotinib Inhibits HER2 exon 20 Insertion Mutations in Vitro and In Vivo 
Figure 6 and  Figure 7 present the results of recent in vitro nonclinical studies of poziotinib on 
HER2 exon 20 mutations in NSCLC and other malignancies. Ba/F3 cells with HER 2 exon 20 
insertion A775insYVMA were screened with TKIs including poziotinib. Ba/F3 expressing this 
insertion mutation showed marked sensitivity to poziotinib (Figure 6) [10, 11]. We found that 




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after drug treatment for 72 hours (C-E). Dots are representative of mean ± SEM (N≥3). (F) Bar graph of MCF10A HER2 mutant 
to WT ratio where dots are representative of mean ± SEM for each cell line and bars are representative of mean ± min/max of all 
three cell lines. 
In addition, human breast and colorectal cell lines and xenografts with HER2 mutations were 
highly sensitive to poziotinib in vitro and in vivo (Figure 8). Poziotinib is 2.6 and 19 times more 
potent than tarlox-TKI and neratinib, respectively (Figure 8A-C). Poziotinib was the most mutant 
selective TKI tested in MCF10A cell lines, followed by pyrotinib, and tarlox-TKI (Figure 8D). 
In a model of HER2 exon 19 mutant colorectal cancer (CW-2), differences in sensitivity between 
poziotinib, tarlox-TKI, and neratinib were less dramatic, albeit significant (p=0.02 and 
p=0.0004) with average IC50 values of 3.19nM, 4.24nM, and 68.8nM, respectively (Figure 8F) 
[10]. 
Figure 8 Human Breast and Colorectal Cell lines with HER2 Mutations Highly Sensitive 
to Poziotinib in Vitro and in Vivo 
 
 
(A-C) Dose response curves of MCF10A cells expressing exon 20 insertion mutations or (D) CW-2 cells treated with indicated 
inhibitors for 72 hours. (E) Tumor growth curve of CW-2 cells (HER2 L755S) xenografts treated with indicated inhibitors. Two-
Way ANOVA was used to determine statistical significance. Asterisk indicate significance between vehicle and poziotinib (red) 
or neratinib (grey). (F) Bar graph of CW-2 tumor volume at day 21. Dots are representative of individual tumors, and bars are 
representative of mean ± SEM. The dotted line indicates randomization at 350mm3.  Statistical significance was determined by 
one-way ANOVA. 
Moreover, poziotinib led to the suppression of HER2 phosphorylation and decreased 
downstream signaling, that was associated with an increased level of cleaved PARP suggesting 
that treatment with poziotinib leads to cell apoptosis (Figure 9) [9]. 


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Figure 9 Effect of Poziotinib (HM781-36B) on HER2 Phosphorylation and Downstream 
Signaling 
 
Western blotting confirms inhibition of p-HER2 in Ba/F3 cell lines after 2 hours of poziotinib treatment (n=2) 
In vivo studies were also conducted to test the effect of poziotinib in genetically-engineered mice 
with HER2 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 10A and B) [11]. 


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Figure 10 MRI Results after Poziotinib Treatment  
 
A) Waterfall plots of HER2 GEMM tumor volume change as measured by MRI after 4 weeks poziotinib treatment 
B) DMRIs of HER2 GEM before and after 4 weeks poziotinib treatment.  
In addition, in a model of HER2 exon 19 mutant colorectal cancer (CW-2), poziotinib 
demonstrated most potent inhibitory activity among other TKIs.  Furthermore, in a xenograft 
mouse model of CW-2 colorectal cells, poziotinib treated animals had shown a significant tumor 
growth inhibition (TGI) (unpublished manuscript). 
1.1.2.4.1 Poziotinib Absorption, Distribution and Metabolism  
Poziotinib exhibits high plasma clearance, moderate oral bioavailability, high protein binding, 
slow metabolism in vitro, and extensive metabolism in vivo. Exposure to poziotinib increased 
with increasing dose, and pharmacokinetic profiles were similar between males and females in 
Pre=Poziotinib
After 4 Weeks Poziotinib 
Treatment
4 Weeks Poziotinib Treatment
Vehicle
Poziotinib
A
B


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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 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 [12]. 
1.1.2.4.2 Poziotinib Toxicity Studies 
The toxicology of poziotinib has been evaluated in animal studies and 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 [9-12], 
suggesting that poziotinib toxicity is a class effect of EGFR tyrosine kinase inhibition.  
1.1.2.5 Poziotinib Clinical Studies 
The clinical development program for poziotinib is ongoing in collaboration with Hanmi 
Pharmaceuticals, Inc. in Korea.  To date, 10 studies have been conducted in Korea. Three of 
these are Investigator-initiated studies and are ongoing. The remaining seven trials have been 
completed and are listed below.  
Poziotinib Clinical Trials Completed in Korea: 
• Two (2) Phase 1 studies (HM-PHI-101 & HM-PHI-102) conducted in patients with 
advanced cancers (solid tumors) are PK/PD and dose finding studies 
• Four (4) Phase 2 studies (NOV12010-201, NOV120101-202, HM-PHI-A201, and 
NOV12010-203) conducted in patients with EGFR-mutant NSCLC, advanced gastric 
cancer, and HER2+ breast cancer 
• Investigator-Initiated study (NSCLC with HER2 mutations).  
Ongoing Poziotinib Trials in the US: 
• Phase 1 study (SPI-POZ-101) in HER2+ breast cancer in combination with T-DM1 
• Phase 2 study (SPI-POZ-201) in HER2+ breast cancer with ≥2 prior HER2 directed 
therapies 
• Phase 2 study (SPI-POZ-202) in NSCLC with EGFR or HER 2 exon 20 insertion 
mutation in pretreated and treatment naïve patients 
• Phase 2, US Investigator-Initiated Study (NCT03066206) in NSCLC with EGFR or 
HER2 exon 20 mutation 
The maximum tolerated dose was determined in two different Phase I studies. In the HM-PHI-
101 study, poziotinib was administered on an intermittent schedule (2 weeks on and 1 week off) 
at doses ranging from 0.5 mg to 32 mg, and the maximum tolerated dose was determined as 24 
mg in this schedule. In the HM-PHI-102 study, poziotinib was administered daily at doses 


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ranging from 12 mg to 24 mg. In this study, the maximum tolerated dose was determined as 18 
mg, and the recommended dose was 16 mg. This is the basis for selecting the 16 mg dose for 
lung cancer studies where the drug is administered daily.Overall, 1143 patients have received 
poziotinib in 21 clinical studies (12 sponsored by Hanmi, 8 Sponsored by Spectrum, and 1 by 
MD Anderson Cancer Center) at doses ranging from 0.5 mg to 32 mg QD on an intermittent 
dosing schedule or 10 mg to 24 mg QD on a continuous dosing schedule. Combined, more than 
500 patients have been treated orally with 16 mg QD as their starting daily dose representing a 
large safety dataset for this rare mutation. Poziotinib as monotherapy is being studied in NSCLC 
patients with EGFR and HER2 exon 20 mutations in an open-label, single-arm study Phase 2 
study at the University of Texas MD Anderson Cancer Center (MDACC) (NCT03066206). In 
this study, a cohort of 50 patients with previously treated, locally advanced or metastatic NSCLC 
bearing mutations in EGFR exon 20 (except EGFR T790M) and another cohort of 30 patients 
with NSCLC HER2 exon 20 mutations were to be enrolled. The preliminary data on 50 patients 
in EGFR exon 20 cohort and 13 patients in HER2 exon 20 Cohort was presented at the 
International Association for the Study of Lung Cancer (IASLC) 2018.  This phase 2 study 
demonstrated high anti-tumor activity for poziotinib with best response of PR in 55% of 
evaluable patients (43% confirmed ORR to date) in metastatic, heavily pretreated EGFR exon 20 
mutant NSCLC Cohort (Figure 11) and showed an initial response in 50% (6/12) of evaluable 
HER2 exon 20 mutations patients to date [6].  
Figure 11 Poziotinib efficacy in patients with EGFR exon 20 mutant NSCLC  
 
 
One of the patients with NSCLC harboring HER2 exon 20 (Y772dupYVMA) mutation who has 
been treated with poziotinib. The CT scans of this patient showed one (1) day before poziotinib 
treatment and 8 weeks after poziotinib therapy (Figure 12) (J. Heymach’s unpublished data) 
 




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Figure 13 
CT of Abdomen, 
 
Figure 14 CT of Abdomen,
 
This patient received poziotinib therapeutic benefit for about 6 months with clinical 
improvement and imaging/biomarker confirmation [13]. 
1.1.2.5.1.2 Case 2 – NSCLC with HER2 Exon 19 Mutation 
The second case was a 
-year-old man and was a former smoker. He was diagnosed in 
 with adenocarcinoma of the right lower lung and underwent a right lower 
lobectomy. He received 4 cycles of adjuvant chemotherapy with cisplatin and pemetrexed in 
. 
From 
, he had disease recurrence in the mediastinum and pleura which was 
biopsied and confirmed to be an adenocarcinoma. Molecular profiling diagnosed an ERBB2 
(HER2) exon 19 L755P mutation. He received 6 cycles of carboplatin, pemetrexed and 




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stomatitis (64.5%), and rash (48.4%). The most common TEAEs in Cohort 2 were diarrhea 
(73.7%), stomatitis (47.4%), and rash (52.6%). Diarrhea, stomatitis, and rash were also the most 
common treatment-related TEAEs in both cohorts. 
In SPI-POZ-202, Cohort 5, poziotinib is being administered at varying doses (10 mg QD, 6 and 8 
mg BID) to patients with NSCLC with EGFR and HER2 mutations. Patients treated with 8 mg 
BID have demonstrated improved tolerability and safety as compared to once daily dosing with 
16 mg QD. As shown in Figure 16, patients treated with 8 mg BID had reduced treatment 
emergent ≥Grade 3 AES and treatment-related AEs [Le et al, 2021]. Preliminary response data 
also showed improved anti-tumor activity with 8 mg BID dosing compared to 10, 12, 16 mg QD 
or 6 mg BID. Patients are continuing to be enrolled at the 8 mg BID starting dose.  
Figure 16  
Safety Comparison of 16 mg QD vs 8 mg BID 
 
 
1.2 Rationale for the Current Study 
Many solid tumors, including lung, breast, bladder, head and neck, and other gastro-intestinal 
cancers, are associated with either an activating mutation in or overexpression of members of 
the ErbB receptor family, especially EGFR and HER2 [2]. Treatments that specifically target 
HER2 overexpression have been shown to be particularly beneficial to breast cancer patients 
and several targeted therapies have been approved by the FDA to treat EGFR mutant NSCLC. 
However, to date, excluding NSCLC, there are no FDA-approved targeted therapies for EGFR 
or HER2 mutant solid tumors. The results of nonclinical in vitro and in vivo studies indicate 
high sensitivity of both EGFR and HER2 activating mutations (including exon 20 insertion, 


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other point mutations in the kinase domain) across tumor types to poziotinib, a novel oral, 
irreversible pan-HER inhibitor ([10], [4] and Study Report Dv-0080). Clinical efficacy and 
safety data obtained to date indicate that poziotinib may be beneficial to patients with lung and 
breast cancers that harbor EGFR or HER2 mutations ([5], [6] and Case Reports in Section 
1.1.2.5.1). Based on the Phase 1 study, HM-PHI-102, the recommended Phase 2 dose is 16 mg 
daily. Combined, more than 260 patients have been treated with 16 mg as their starting dose. 
Poziotinib was well tolerated by majority of patients. Therefore, the current multi-center basket 
study is planned to evaluate 16 mg daily poziotinib in patients with EGFR and HER2-
mutatation positive solid tumors in 5 different cohorts. 
2 STUDY OBJECTIVES  
2.1 Primary Objective 
• To evaluate the Objective Response Rate (ORR) of poziotinib in patients with EGFR or 
HER2 mutation-positive malignant solid tumors 
2.2 Secondary Objectives 
• To evaluate other efficacy variables of poziotinib in patients with EGFR or HER2 
mutation-positive, malignant solid tumors, including the following: 
• 
Duration of Response (DoR) 
• 
Disease Control Rate (DCR)  
• To evaluate the Safety and Tolerability of poziotinib in patients with EGFR or HER2 
mutation-positive malignant solid tumors 
2.3 Exploratory Objectives 
• To evaluate the following additional efficacy outcomes: 
• 
ORR, DCR, and DoR in patients with baseline CNS metastases 
• 
Overall Survival (OS) and Progression-free Survival (PFS) 
• 
Relationship between molecular biomarkers and clinical outcome 
3 INVESTIGATIONAL PLAN 
3.1 
Study Design and Treatment Plan 
This is a Phase 2 multicenter, open-label study to evaluate the efficacy and safety of poziotinib in 
patients with eligible EGFR or HER2 mutation-positive malignant solid tumors.  
The study is a basket trial with five patient cohorts. The primary analysis will be conducted for 
each cohort separately. The five patient cohorts are:  
• Cohort 1: Patients that have HER2-positive or HER2-negative breast cancer with HER2 
activating mutations (see Table A in Section 4.1) (N=30) (See Inclusion Criteria #4) 
• Cohort 2: Patients that have colorectal cancer with HER2 activating mutations (see 
Table A in Section 4.1) (N=30)  


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• Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal 
cancer) with HER2 activating mutations (see Table A in Section 4.1) (N=30) 
• Cohort 4: Patients that have GBM with EGFR activating mutations (see Table A in 
Section 4.1) (N=30) 
• Cohort 5: Patients that have solid tumors (except NSCLC or GBM) with EGFR 
activating mutations (see Table A in Section 4.1) (N=30) 
This study includes a two-stage design in each cohort separately. The first-stage of each cohort 
will enroll 9 patients. Details of the two-stage design are provided in the statistical section. A 
cohort will enroll patients into the second-stage if the required responses are observed in 9 
patients in the first-stage for each cohort. 
The Screening period (Day -30 to Day 1) lasts up to 30 days prior to Cycle 1, Day 1. Patients 
must provide written Informed Consent prior to undergoing any study procedure. Patients must 
meet all Inclusion/Exclusion Criteria to participate in the study. Each treatment cycle is 28 
calendar days in duration, regardless of dosing interruptions. Tumor assessments are scheduled at 
Baseline/pre-dose, Week 4, Week 8 and every 8 weeks thereafter. In the event of a response (PR 
or CR), a confirmatory scan may be performed 4 weeks from the initial response. Pre-dose tumor 
assessments must be within 14 days prior to Cycle 1, Day 1 (Baseline assessments may be used 
if obtained within 14 days prior to Cycle 1, Day 1). 
The treatment period for all patients will be from the time of the first dose of poziotinib to the 
first occurrence of disease progression, intolerable adverse events, the start of a new anti-cancer 
treatment, or death.  
Following radiological progression, the patient may continue to receive poziotinib in an 
Extension Study (SPI-POZ-501) only if the following criteria are met: absence of signs and 
symptoms indicating clinical deterioration due to progression of disease or drug toxicity and no 
decline in ECOG or performance status or if the investigator and medical monitor agree that the 
patient continues to derive clinical benefit. Disease imaging assessments must continue at the 
institutional standard of care interval. In addition, the patient will be made aware of other 
therapeutic options and reconsented if their decision is to continue poziotinib. 
SPI-POZ-501 Extension Study: Patients who wish to participate in the extension study must 
provide written Informed Consent. Treatment will begin after the patient has completed the End-
of-Treatment (EOT) Visit in the Original Study (ie visit in SPI-POZ-203 study). Assessments 
obtained at the EOT visit in the Original Study will serve as Baseline data for the extension 
study.  
Patients will continue to receive poziotinib at the last dose level and schedule received in the 
POZ-203 study. Poziotinib dose modifications will be allowed under the treating physician’s 
discretion after consultation and approval from the Spectrum medical monitor.  
Safety will continue to be followed during the extended treatment according to Standard of Care 
(SOC). Efficacy of continued poziotinib treatment will be evaluated by imaging according to the 
Institution’s SOC, but at least every 2 cycles.  
A patient may continue to receive poziotinib treatment as long as the patient is deriving clinical 
benefit, as judged by consensus of the investigator and Spectrum medical monitor, or until 
withdrawal of consent, unacceptable toxicity, the patient is lost to follow-up, poziotinib receives 
commercial approval in their country of residence, or development of poziotinib is terminated by 


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the Sponsor, whichever occurs first. There will be an End-of-Treatment (EOT) Visit 30 (±5) days 
after the last dose of poziotinib. 
3.2 
Study and Treatment Duration  
The total duration of the study will be approximately 4 years although patients will be treated 
until meeting a discontinuation criterion. The duration of study participation for each patient 
includes the following:  
• Screening Period: Up to 30 days 
• Treatment Period: 28 days per cycle or until death, intolerable adverse events, 
progressive disease or other protocol-specified reasons for patient withdrawal  
• End-of-Treatment Visit: 30 (±5) days after the last dose of poziotinib  
• Long-Term Follow-up: After treatment period discontinuation in Study SPI-POZ-203, 
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 
 
The study design diagram is presented in Figure 17 and the Schedule of Study Assessments and 
Procedures is presented Appendix 1. 
 
Figure 17 
 
Diagram of Study Design 
 
4 PATIENT POPULATION  
The following inclusion and exclusion criteria must be met in order to participate in the study. 
Cohort 1: Patients that have HER2-positive or HER2-negative breast cancer with HER2 activating mutations (see Table A) (N=30)
Cohort 2: Patients that have colorectal cancer with HER2 activating mutations (see Table A) (N=30)
Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with HER2 activating mutations (see Table A) (N=30)
Cohort 4: Patients that have GBM with EGFR activating mutations (see Table A) (N=30)
Cohort 5: Patients that have solid tumors (except NSCLC or GBM) with EGFR activating mutations (see Table A) (N=30)
Poziotinib 8 mg PO bid +
Loperamide 4 mg bid or tid
Assess Tumor Response with plasma sample collections 
at Week 4, Week 8 and every 8 weeks thereafter
• Tumor assessment (CT, PET/CT, or MRI for non-brain 
organs and brain MRI)
• Plasma sample collection
Continue Poziotinib until Progressive Disease,  
Intolerable Adverse Events, Death, or the Start of a 
new Anti-cancer Treatment up to 24 months
Baseline Imaging (CT, PET/CT, or MRI for 
non-brain organs and brain MRI)
Tissue procurement, if possible
Plasma sample collection
Blood sample collection 
End of Treatment Visit
30 (±5) Days After Last Dose


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4.1 Inclusion Criteria: 
1. Males or females 18 years of age or older 
2. Patient must be willing and capable of giving written Informed Consent, adhering to 
dosing and visit schedules  
3. Patient has an advanced or metastatic solid tumor with no available standard therapy 
option 
4. Patients with breast cancer must have an NGS HER2 activating mutation (see Table A), 
and: 
• IHC HER2-positive tumors (based on ASCO/CAP criteria) are included only when 
they have progressed on trastuzumab, pertuzumab, and T-DM1 which have been 
administered in the metastatic setting, unless disease recurred within 12 months of 
adjuvant or neoadjuvant treatment. 
• IHC HER2-negative, ER/PR-positive breast cancer (based on ASCO/CAP criteria) 
may be included after 1st line endocrine therapy in the metastatic setting, either as a 
single agent or in combination with standard biological agents (eg aromatase inhibitor 
and CDK 4/6 inhibitor). Patients are permitted to continue single agent endocrine 
therapy concurrently with the study. 
• IHC HER2-negative, ER/PR-negative tumors may be included after first-line 
treatment (any standard chemotherapy-based regimen) in the metastatic setting.  
5. Patient with colorectal cancer who are MSI-H and have confirmed progression on 
pembrolizumab or nivolumab or nivolumab/ipilimumab 
6. Patient’s tumor is positive for eligible EGFR or HER2 mutations based on DNA genetic 
testing of either tumor tissue or plasma samples. Patients with documented EGFR or 
HER2 mutations are identified by local testing from participating sites using next 
generation sequencing (NGS) test such as OncoMine Comprehensive Assay (OCA), 
Guardant360 Assay, or FoundationOne Assay that detects specific mutations, performed 
by a US CLIA certified and CAP accredited clinical laboratory or similarly accredited lab 
for ex-US sites using tissue or plasma samples.  Patient has a solid tumor with at least one 
of the listed activating mutations (see Table A):  
• Cohort 1: Patients that have HER2-positive or HER2-negative breast cancer with 
HER2 activating mutations (see Table A) (N=30) (See Inclusion Criteria #4) 
• Cohort 2: Patients that have colorectal cancer with HER2 activating mutations (see 
Table A) (N=30) 
• Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal 
cancer) with HER2 activating mutations (see Table A) (N=30) 
• Cohort 4: Patients that have GBM with EGFR activating mutations (see Table A) 
(N=30) 
• Cohort 5: Patients that have solid tumors (except NSCLC or GBM) with EGFR 
activating mutations (see Table A) (N=30) 
Table A—List of Activating Mutations Eligible for Enrollment 




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• Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), 
alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) 
≤2.5×upper limit of normal (ULN); if hepatic metastases are present, ≤5.0×ULN 
• Creatinine clearance 
• Creatinine clearance ≥ 50 mL/min (calculated according to Cockcroft and 
Gault formula: CCr = {((l 40–age) x weight)/(72xSCr)}) x 0.85 (if 
female), Scr in mg/dL) 
or  
• GFR >= 45 ml/min/1.73m2 as calculated by the CKD-EPI Creatinine 
Equation (2009) 
(https://www.kidney.org/professionals/kdoqi/gfr_calculator)  
11. Patient with childbearing potential is willing to practice 2 forms of contraception, one of 
which must be a barrier method, from study entry until at least 30 days after the last dose 
of poziotinib.  
12. Females of childbearing potential must have a negative serum pregnancy test within 
7 days prior to study treatment. Females who are postmenopausal do not require this test 
(Postmenopausal is defined as any of:  age >60 years, age <60 years and amenorrheic for 
12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian 
suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal 
range, or prior bilateral oophorectomy, or if taking tamoxifen or toremifene, or age <60 
years with FSH and plasma estradiol in postmenopausal ranges). 
4.2 Exclusion Criteria:  
1. Patient has primary tumors in central nervous system (CNS), meningeal carcinomatosis, 
leptomeningeal carcinomatosis, spinal cord compression, or unstable brain metastasis 
except if qualified under inclusion criteria for Cohort 4.  
2. Patients with the T790M mutation in EGFR.  
3. Patients with breast or gastric cancers without eligible HER2 mutations (see Table A).  
4. Patient has received anticancer chemotherapy, biologics, immunotherapy, targeted 
therapy (including HER2 targeted therapy), curative-intent radiotherapy, or other 
investigational treatment within 15 days of study entry. Palliative local radiation therapy 
for bone metastasis may be allowed. Standard and approved hormonal therapies for 
hormonal receptor positive tumors are allowed. For Cohort 4, patients who have received 
prior single agent VEGF inhibitor therapy (eg bevacizumab) are excluded. 
5. Patient has used or will continue to use strong inhibitors/inducers of CYP3A4 and 
CYP2D6 within 2 weeks prior to or during the study. 
6. Patient has not recovered (i.e, > Grade 1) from drug-induced pancreatitis or has a history 
of drug-induced pancreatitis. 
7. Patient has interstitial lung disease (ILD) or history of ILD or pneumonitis or is less than 
30 days from last dose of CPI. 
8. Patient has ≥ Grade 2 skin disorders (rash), mucositis, or stomatitis within previous 15 
days.  


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9. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New 
York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias 
requiring treatment. 
10. Patient has a high risk of cardiac disease, as determined by the Investigator. If patient is 
deemed to have a high cardiac risk, enrollment may be considered if echocardiogram 
(ECHO) or multi-gated acquisition (MUGA) during Screening demonstrates a cardiac 
ejection fraction >50%. 
11. Patient has a QTc > 470 ms. 
12. Patient has a history of other malignancies within the last 1 year, except for non-
melanoma skin cancer, carcinoma in situ of the cervix, or PSA-stable, asymptomatic 
early stage prostate cancer or superficial bladder cancer without active treatment.  
13. Patient has clinically significant or recent acute gastrointestinal disease presenting as 
diarrhea and/or coloenteritis as the main symptom (i.e. acute enteritis, malabsorption, or 
Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) Grade 2 or 
higher diarrhea due to other drug-related reasons within 15 days. 
14. Patient is unable to take drugs orally due to disorders that may affect gastrointestinal 
function or has malabsorption syndrome. 
15. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, 
asymptomatic biliary stones, liver metastasis, or stabilized chronic liver disease).  
16. Patient has a medical condition that in the opinion of the investigator or medical monitor 
would put her/him at an unreasonable risk during the trial.  
17. Patient has known hypersensitivity to poziotinib or history of allergic reactions attributed 
to a compound of similar chemical composition to poziotinib.  
18. Patient has an active or uncontrolled infection, active bleeding disorder, any underlying 
medical condition, or other serious illness that would impair the ability of the patient to 
receive protocol treatment. 
19. Patient has had recent major surgery or invasive procedure within 15 days prior to 
starting study treatment. 
20. Patient is pregnant or breast-feeding. 
4.3 Patient Discontinuation/Withdrawal Criteria  
Patients can withdraw from participation in this study at any time, for any reason, specified or 
unspecified, and without prejudice.  
All treated patients must be withdrawn from the study due to 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 study drug 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 an End-of-Treatment Visit 30 (±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. 
Patients not efficacy evaluable i.e. not completed at least 1 cycle of poziotinib treatment and 
have baseline and at least 1 post-baseline tumor response evaluation using RECIST, version 1.1 
(and/or RANO for Cohort 4) will be replaced unless they have discontinued from treatment or 
from the study due to disease progression or probable disease progression (eg. clinical 
progression, initiation of new therapy) or due to toxicity. 
5 STUDY PROCEDURES  
Refer to the Schedule of Study Assessments and Procedures presented in Appendix 1. 
5.1 Screening 
Informed Consent is to be obtained prior to the start of any protocol-specified assessments or 
procedures. The procedures and evaluations required for enrollment into the study are 
summarized below. All potential study patients will be screened, and eligibility determined prior 
to enrollment. The results of any procedures or laboratory assessments performed prior to the 
signing of Informed Consent as part of the site’s routine standard of practice will be allowed for 
use as a Screening Assessment at the discretion of the Sponsor. This information is to be 
discussed with the Medical Monitor before the patient is enrolled in the study.  
Patients must have disease that is resistant to or relapsed following available standard systemic 
therapy (according to NCCN or ASCO guidelines), or for which there is no standard systemic 
therapy or reasonable therapy in the physician’s judgment likely to result in clinical benefit or if 
such therapy has been refused by the patient. Documentation of the reason must be provided for 
patients who have not received a standard therapy likely to result in clinical benefit. 
All procedures are to be performed as outlined in Appendix 1 prior to the start of study 
treatment, unless otherwise noted.  
5.2 Patient Assignment 
Confirmation of eligibility is to be received by the investigational site from Spectrum prior to 
enrollment of a patient. After a patient has signed the ICF, the Investigator or site staff should 
assign a Patient ID. The Patient ID will include two parts: the site number assigned by Spectrum 
will be comprised of 5 digits with a 2-digit alphabetic country code [Reference ISO 3166] 
followed by a 3-digit site specific numeric code and a hyphenated 3-digit patient sequential 
number, unique to a site, separated by a hyphen (i.e., US001-001).  
A CRF will only be completed for patients who are enrolled and receive a Patient ID.  


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5.3 Timing of Assessments and Procedures 
5.3.1 Screening Visit (Within 30 Days of Cycle 1, Day 1) 
The following screening assessments should be performed within 30 days prior to Cycle 1, 
Day 1. Obtain Informed Consent prior to any study procedures.  
• Informed Consent 
• Patient ID 
• Relevant medical history 
• Demographic data 
• Height and weight 
• Complete physical examination 
• Vital signs 
• Eastern Cooperative Oncology Group (ECOG) Performance Status assessment 
• Pregnancy test (blood beta-human chorionic gonadotropin [β-HCG]) in women of 
childbearing potential  
• Tumor assessment: Screening tumor assessment for patient eligibility will be based on 
scans performed locally within 30 days before the patient signed the ICF; Baseline tumor 
assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI) will be 
performed within 2 weeks prior to, or on Cycle 1, Day 1 
• Tumor histopathology report (from local pathologist) and molecular test report for 
mutation diagnosis 
• Complete blood count (CBC) with 5-part differential and platelets prior to poziotinib 
administration (may be obtained up to 7 days prior to Cycle 1, Day 1)  
• Serum chemistry prior to poziotinib administration (may be obtained up to 7 days prior to 
Cycle 1, Day 1) 
• Electrocardiogram (ECG) 
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction (only for patients 
who have a high risk of cardiac disease, as determined by the Investigator) 
• Tissue sample (from archival or fresh biopsy) or plasma for tumor genotyping 
• Plasma sample for biomarker analysis  
• Whole blood sample for pharmacogenomic analysis  
• Adverse event assessment using NCI CTCAE, version 5.0. Only study-related SAEs to 
be recorded during Screening 
• Concomitant medication review 
5.3.2 Treatment Period – Cycle 1, Day 1  
• Eligibility confirmation 
• Height and Weight  
• Physical examination 
• Vital signs  


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• ECOG Performance Status assessment 
• Urine 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 
• Serum Chemistry 
• Intense pharmacokinetic sampling (see schedule of sampling in section 5.4.6) 
• ECG before each PK sampling 
• Dispense poziotinib and loperamide  
• Adverse event assessment using NCI CTCAE, version 5.0  
• Dispense Patient Diary  
• Concomitant medications review 
5.3.3 Treatment Period – Cycle 1, Days 8 and 15 (±3 Days) 
• Physical exam 
• Vital signs 
• Complete blood count with 5-part differential and platelets 
• Intense pharmacokinetic sampling can occur only on C1D8 +/- 3 days (see schedule of 
sampling in section 5.4.6) 
• ECG before each PK sample on Day 8 only 
• Adverse events using NCI CTCAE, Version 5.0 
• Patient Diary Review 
• Concomitant medications review 
• Contact patient by telephone calls between Day 3- 8 for any AE, such as skin rash and 
diarrhea, and take action according to Appendices 3, 4, and 5 
5.3.4 Treatment Period – Cycle 1, Day 22 (±2 Days) (By Telephone) 
• Adverse event assessment using NCI CTCAE, Version 5.0  
• Concomitant medications  
5.3.5 Treatment Period – Cycle 2, Day 1  
• Height and Weight  
• Physical examination 
• Vital Signs 
• ECOG Performance Status assessment 
• Urine pregnancy test in women of childbearing potential  
• Tumor assessment: either CT, PET/CT, or MRI for non-brain organs and brain MRI (the 
same imaging acquisition method as the baseline should be used)  
• Complete blood count with 5-part differential  


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• Serum chemistry 
• Plasma sample for biomarker analysis 
• Dispense poziotinib and loperamide 
• Adverse event assessment using NCI CTCAE, Version 5.0 
• Dispense and Collect Patient Diary 
• Concomitant medications review 
5.3.6 Treatment Period – Cycle 2, Day 8 (±1 Day) 
• Complete blood count with 5-part differential and platelets 
• Adverse event assessment using NCI CTCAE, Version 5.0; a telephone call to patient for 
the follow up of AEs between Days 3 to 8 
• Patient Diary review  
• Concomitant medications review 
5.3.7 Treatment Period – Cycle 3+, Day 1 
• Weight  
• Physical examination 
• Vital Signs 
• ECOG Assessment 
• Urine pregnancy test in women of childbearing potential 
• Tumor assessment: either CT, PET/CT, or MRI for non-brain organs and brain MRI 
(unless the patient has documented disease progression or has undergone a tumor 
assessment with the previous 8 weeks; the same imaging acquisition method as the 
baseline should be used)  
• Complete blood count with 5-part differential  
• Serum chemistry 
• Plasma sample for biomarker analysis 
• Dispense poziotinib and loperamide 
• Adverse event assessment using NCI CTCAE, Version 5.0 
• Dispense and Collect Patient Diary 
• Concomitant medications review 
5.3.8 End-of-Treatment Visit (30 [±5] Days After Last Dose of Study Treatment) 
The End-of-Treatment Visit is required 30 (±5) days after the last dose of poziotinib is 
administered. The following assessments are to be performed at this visit:  
• Height and Weight 
• Physical examination 
• Vital signs  


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• ECOG Performance Status assessment 
• Urine pregnancy test in women of childbearing potential  
• Tumor assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI 
(unless the patient has documented disease progression or has undergone a tumor 
assessment within the previous 8 weeks; same imaging acquisition method as the baseline 
should be used)  
• CBC with 5-part differential and platelets  
• Serum chemistry  
• Newly biopsied tumor tissue taken from patients who progress for biomarker analysis 
(optional, but encouraged) 
• Plasma sample for biomarker analysis if the patient progresses (optional) 
• Adverse event assessment using NCI CTCAE, Version 5.0 
• Patient Diary Collection 
• Concomitant medications review 
5.3.9 Long-Term Follow-up – Every 3 Months  
• After progressive disease is documented, regardless of possible treatment continuation, 
patients who have consented will be contacted by phone or email (or letter if specifically 
requested) every 3 months, for up to 2 years after patient’s first dose of poziotinib, for 
survival assessment  
• Record SAEs where a causal relationship with the study drug is suspected. 
5.4 Description of Study Assessment Parameters 
5.4.1 Relevant Medical History 
At Screening Visit, the patient’s relevant medical history will be collected, to include previous 
therapy, as well as significant and relevant past diseases and current medications.  
5.4.2 Physical Examination 
A complete physical examination, including a description of external signs of the neoplastic 
disease and co-morbidities, will be performed at Screening Visit, Cycle 1, Days 1, 8, and 15 and 
Day 1 of each subsequent cycle,  and Day 1 of each cycle, and at the End-of-Treatment Visit. 
Symptom-directed examinations are required at other visits. Physical examinations are to be 
completed by a physician or other health professional licensed to perform 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, Cycle 1, Days 1, 8, and 15 and Day 1 of each subsequent cycle and at the 
End-of-Treatment Visit. Heart rate and blood pressure will be recorded before poziotinib 
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5.4.4 ECOG Performance Status 
Patients’ Performance Status will be evaluated using criteria as developed by the Eastern 
Cooperative Oncology Group (Appendix 2) at Screening and Day 1 of each cycle and at the 
End-of-Treatment Visit.  
5.4.5 Clinical Laboratory Tests 
A local laboratory will be used to process all clinical specimens. The following clinical 
laboratory parameters will be evaluated in this study: 
• Complete Blood Count (CBC): A CBC, including white blood cells (WBC), with 5-part 
differential, hemoglobin, and platelets will be performed at Screening, Day 1 and Day 8 
of Cycle 1 and Cycle 2, Day 1 of each cycle, and at the End-of-Treatment Visit. The 
results of the laboratory assessments should be evaluated and medically accepted by the 
responsible physician before the start of each cycle.  
• 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, uric acid, and glucose, will be performed at Screening Visit, 
Day 1 of each cycle, and at the End-of-Treatment Visit.  
• 
Special note for the Day 1 sampling of each cycle: If possible, blood samples 
should be drawn on Day 1 of each cycle (prior to treatment); however, for logistical 
reasons, it is also acceptable to draw samples for assessment up to 7 days prior to the 
start of a cycle. The results of the laboratory assessments should be evaluated and 
medically accepted by the responsible physician before the start of each cycle. 
• Pregnancy Test: A blood β-hCG test will be performed for all women of childbearing 
potential at Screening. A urine pregnancy test is required on Day 1 of each Cycle starting 
from Cycle 2 and at Cycle 1, Day 1, if Screening pregnancy test was more than 7 days 
prior to Day 1. Urine pregnancy test also required at End-of-Treatment Visit. 
5.4.6 PK Sample 
At select study centers, up to 25 patients may be specifically consented for intensive PK 
sampling and concurrent ECGs as defined below:  
Schedule:  Intensive PK blood sampling will be at pre-dose and 2, 4, 8, 12, and 24 hours post-
dose on Cycle 1, Day 1 and on Cycle 1, Day 8 (±3 days). The 12-hour and 24-hour PK samples 
must be collected prior to the second daily dose. A local 12-lead ECG will be obtained just 
before each PK blood sample on both Day 1 and Day 8. If the patient has interrupted continuous 
poziotinib dosing, clear dosing documentation must be done in order to assess suitability of 
further PK sampling and ECG recording.  
In addition, if a patient presents with a potentially drug-related Grade ≥3 AE, a PK sample 
should be collected as soon as possible, if feasible, following the onset of the AE in order to 
characterize the PK. Documentation of last dose timing prior to the event is required.  


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5.4.7  Electrocardiogram (ECG) 
A 12-lead ECG will be performed at Screening. At select study centers, up to 25 patients may be 
specifically consented for intensive PK sampling and concurrent ECGs as defined below:  
Schedule:  Intensive PK blood sampling will be at pre-dose and 2, 4, 8, 12, and 24 hours post-
dose on Cycle 1, Day 1 and on Cycle 1, Day 8 (±3 days). The 12-hour and 24-hour PK samples 
must be collected prior to the second daily dose. A local 12-lead ECG will be obtained just 
before each PK blood sample on both Day 1 and Day 8. If the patient has interrupted continuous 
poziotinib dosing, clear dosing documentation must be done in order to assess suitability of 
further PK sampling and ECG recording.  
In addition, if a patient presents with a potentially drug-related Grade ≥3 AE, a PK sample 
should be collected as soon as possible, if feasible, following the onset of the AE in order to 
characterize the PK. Documentation of last dose timing prior to the event is required.  
5.4.8 Cardiac Ejection Fraction 
For patients who are at high risk of cardiac disease, as determined by the Investigator, cardiac 
ejection fraction may be assessed by either echocardiogram or multi-gated acquisition (MUGA) 
scan at Screening, and the investigator can order subsequent tests based on institutional standard 
of care.  
5.4.9 Tumor Assessment 
Tumor assessment for study patient’s eligibility must be performed by Investigators using 
computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance 
imaging (MRI) for non-brain organs and MRI for brain at Screening up to 30 days prior to 
Cycle 1, Day 1. Imaging studies performed prior to the signing of Informed Consent as part of 
the site’s routine standard of practice are allowed at the discretion of the Sponsor as the 
Screening assessment. Brain MRI must be performed to assess the brain metastasis status at the 
screening per eligibility criteria. This information is to be discussed with the Sponsor’s Medical 
Monitor before the patient is enrolled in the study. Baseline tumor assessment will be performed 
within 2 weeks prior to, or on Cycle 1, Day 1.  Post-Baseline tumor assessments must be 
performed at Cycle 2 Day 1, at Cycle 3 Day 1, and every 8 weeks thereafter until patient 
discontinuation.  
Each subsequent tumor assessment must use the same radiologic technique as in Baseline, either 
CT, PET/CT, or MRI. Tumor assessments will be made according to RECIST, version 1.1 [14] 
using appropriate radiologic imaging or other techniques. For radiographic assessment, CT, 
PET/CT, or MRI must be performed at every assessment.  
In Cohort 4, tumor assessments will be made using appropriate radiologic imaging techniques as 
per RECIST 1.1 and/or the RANO criteria [15]. 
Measurable and non-measurable lesions should be documented appropriately.  
Tumor assessment is based on the study investigator’s assessment with local radiology review 
and report according to the RECIST 1.1 and/or RANO (for Cohort 4) criteria for response 
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5.4.10 Tissue, Plasma, and Whole Blood Samples Retained  
5.4.10.1 Tissue Samples 
Tissue samples at Screening, if available, are acquired prior to Cycle 1, Day 1 during the 
screening period. If possible, tumor tissue samples from a biopsy when progression occurs 
during the study should be collected. This is not mandatory but is encouraged. The tumor tissue 
will be used for genetic analysis (DNA and or RNA sequencing) to understand poziotinib 
response and resistance mechanisms. 
5.4.10.2 Plasma Samples 
Plasma samples are required at baseline (prior to start of study treatment), and optional on the 
day of each on-study imaging session, beginning at the 8-week imaging session, once every 8 
weeks with imaging scan. The plasma samples will be used for genetic analysis (DNA 
sequencing) to understand poziotinib response mechanism and progression of disease. 
Guardant’s 360 or FoundationACT assays will be used, Plasma sample collection and storage 
will follow vendors’ standard procedures as described in the vendors’ Laboratory Manual. 
5.4.10.3 Whole Blood Samples 
Whole blood samples will be collected once at Screening or during the study for 
pharmacogenomic analysis. 
5.4.11 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 30 (±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.  
5.4.11.1 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 1). 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 




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• Avoidance of spicy, acidic, or irritating foods and alcoholic drinks  
• Use of solutions such as saline (diluted solution with saltwater and baking soda by 
dissolving a ½ teaspoon of salt and 1 teaspoon of baking soda in approximately 1 liter of 
water) and using this solution every 4 hours 
• Use of Nystatin solution 
• Use of Magic Mouthwash (for instance, a combination of viscous lidocaine 2% + 
Mylanta + diphenhydramine elixir + prednisolone solution)  
5.4.11.2.3 Rash Management 
Rash may be managed according to the algorithm in Appendix 4 and/or per standard of care as 
determined by the Investigator or Institutional Guidelines.  
. Supportive intervention, including early steroid use, should be considered even in the presence 
of low-grade “on-target” toxicity (eg, rash, diarrhea).  
5.4.11.2.4 Paronychia management 
Paronychia may be managed according to the algorithm in Appendix 5 and/or per standard of 
care as determined by the Investigator or Institutional Guidelines 
5.4.11.3 Uses of Warfarin or Other Coumadin-Derived Anticoagulants  
Warfarin or other coumadin-derived anticoagulants should be used cautiously during treatment 
with poziotinib. When it cannot be avoided, regular monitoring of INR is required, and prior 
authorization from the Sponsor’s Medical Monitor is required.  
No additional cytotoxic agents, biologic therapy, or immune response modifiers for cure-intent 
purpose are to be administered to patients until study treatment has been discontinued. 
5.4.11.4 Prohibited Therapies or Medications 
No other anti-cancer therapy, including chemotherapy, radiation therapy, immunotherapy, target 
therapy (including HER2 targeted therapy), biologics, or experimental medications, are 
permitted during the trial with the exception of focal radiation therapy for bone pain palliation. Any 
disease progression that requires anti-tumor therapy will be a cause for discontinuation from the 
study. 
6 STUDY DRUG AND PHARMACEUTICAL INFORMATION  
Study treatment is to be handled and administered according to the study sites’ regulations for 
the handling and administration of cytotoxic anticancer agents. 
6.1 Poziotinib 
Poziotinib will be supplied by Spectrum.  
6.1.1 Poziotinib Composition and Formulations 
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet 
for oral administration. Poziotinib tablets are supplied in 2.0-mg and 8.0-mg dose strengths and 
contain 2.0 mg and 8.0 mg of poziotinib hydrochloride salt, respectively. 






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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational drug or a concurrent medication 
• AEs may include pre-treatment or post-treatment events that occur as a result of protocol-
mandated procedures (e.g., invasive procedures) 
Abnormal laboratory results are to be recorded as AEs, if any of the following conditions are 
met: 
• The abnormal laboratory value leads to a therapeutic intervention 
• The abnormal laboratory value is considered to be clinically significant by the 
Investigator 
• The abnormal laboratory value is predefined as an AE in the protocol or in another 
document communicated to the Investigator by Spectrum or designee 
Examples of events that do not constitute AEs include: 
• Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE 
• Situations where an untoward medical occurrence does not occur (e.g., 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 does not worsen  
• Planned and prescheduled hospitalizations and procedures  
• Progressive disease  
The adverse events of special interest identified with poziotinib treatment include diarrhea, skin 
rash, stomatitis, paronychia, and pneumonitis. 
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 30 (±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 30 (±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 
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In addition, the event either occurs immediately following study treatment administration, 
improves on stopping study treatment, reappears on repeat exposure, or there is a positive 
reaction at the application site. 
7.6 Expectedness 
For investigational drugs, an AE is judged “expected” if its description agrees in nature and 
severity with the description of AEs previously noted with the study drug as detailed in the 
current Investigator’s Brochure. An “unexpected” AE is one for which the specificity or severity 
is neither consistent with the current Investigator’s Brochure nor the risk information described 
in the general investigational plan. The Sponsor will be responsible for assessing the 
expectedness of AEs. 
The most common AEs associated with poziotinib treatment include: 
• Diarrhea 
• Rash/Dermatitis acneiform 
• Stomatitis/Mucosal inflammation 
• Paronychia 
• Decreased Appetite  
• Dry Skin 
• Vomiting 
• Pruritus 
 
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: i.e., any event that, in the opinion of the Investigator, poses an 
immediate risk of death to the patient 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 or substantial disruption of the 
ability to conduct normal life functions 
• 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 
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Adverse events that do not meet any of the above criteria for serious should be regarded as non-
serious. 
7.7.1 Serious Adverse Event Reporting 
From the time the study Informed Consent is signed through the first dose of study drug 
administration, only SAEs are to be recorded. All SAEs that occur from the first dose of study 
drug administration through 30 (±5) days after the last dose of study treatment and SAEs that 
occur after 30 (±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: 
Spectrum Pharmaceuticals, Inc. 
Primary Contact: Pharmacovigilance Department 
Fax: +1 (949) 861-6599 
E-mail: drugsafety@sppirx.com 
Spectrum may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports. Safety data that are critical to the reportability of an SAE, 
such as causality assessment and serious criteria, should be included in the initial faxed or 
e-mailed SAER. If omitted, a timely response to drug safety data queries received from Spectrum 
or designee is expected. 
The Investigator is to take all appropriate therapeutic measures necessary for resolution of the 
SAE. Any medications necessary for the 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 (e.g., final diagnosis is made, laboratory or test results, event course, outcome, 
etc).  
The Sponsor or its designee will be responsible for reporting SAEs to the regulatory authorities 
in accordance with applicable expedited reporting regulatory guidelines. The Investigator is 
responsible for submitting SAEs to his/her Institutional Review Board (IRB)/Ethics Committee 
(EC). Copies of each SAER, and documentation of IRB/EC notification and acknowledgement 
of receipt will be kept in the Site’s Regulatory Binder. 
7.7.2 Exclusions to Serious Adverse Event Reporting Requirements 
The following are not considered SAEs: 
• Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, hospitalization for diagnostic tests such as CT 
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• 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.  
• Disease progression as the result of a progressive disease. 
7.8 Reproductive Risks 
No adequate and well-controlled studies of poziotinib have been conducted in pregnant women. 
The effect of poziotinib on fertility and fetal development have not been studied in pregnant 
women. Poziotinib is not recommended for use during pregnancy. 
It is not known whether taking poziotinib can cause death, serious birth defects, or other harm to 
unborn babies or nursing children. Patients should not become pregnant or father a child while 
taking part in this study.  
Any pregnancy involving a study patient or a patient’s partner occurs from the first dose of study 
treatment through 30 days after the last dose of study treatment is to be reported to the Sponsor 
within 24 hours after the Investigator has gained knowledge of the event via fax or e-mail (see 
contact information in Section 7.7.1. Pregnancies should be followed up until outcome and 
follow-up information regarding the outcome of the pregnancy should be faxed or e-mailed to 
Spectrum’s Pharmacovigilance Department.  
All patients who become pregnant during participation in this study will be withdrawn from the 
study. 
8 STATISTICAL PLAN  
A Statistical Analysis Plan (SAP) will be provided before data base lock. 
8.1 Sample Size  
The statistical analysis of each cohort will be performed separately. A total of 30 patients in each 
cohort will be enrolled using Simon’s two-stage design. The optimal two-stage design to test the 
null hypothesis that p≤0.050 versus the alternative that p≥0.250 has an expected sample size of 
16.76 and a probability of early termination of 0.630. If the drug is not effective, there is a 0.049 
probability of concluding that it is (the target for this value was 0.050). If the drug is effective, 
there is a 0.098 probability of concluding that it is not (the target for this value was 0.100). For 
each cohort, 9 patients will be evaluated in the first stage; the cohort will be terminated if 0 
respond. If the cohort goes on to the second stage, a total of 30 patients will be studied. If the 
total number responding is less than or equal to 3, the cohort is closed.  
8.2 Method of Treatment Assignment 
This study is not randomized.  
8.3 Analysis Populations 
The following analysis populations will be defined. 
• The Evaluable Population (EP) consists of all enrolled patients who completed at least 
6 weeks of poziotinib treatment, and have baseline and at least 1 post-baseline tumor 
response evaluation using RECIST, version 1.1 (and/or RANO for Cohort 4) or 


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progressed prior to any post-baseline image evaluation. All efficacy analyses will also be 
done using the Evaluable Population. 
• The Safety Analysis Population (SAF) includes all enrolled patients who received at 
least 1 dose of poziotinib. All demographics, Baseline characteristics, and safety data will 
be analyzed using the SAF population. 
8.4 General Statistical Methods 
The Sponsor’s Biostatistics and Data Management group will be responsible for data 
management and statistical analysis of this study. All statistical analyses will be performed using 
SAS for Windows (Version 9.4 or higher). Patient data listings and tabular presentations of 
results will be provided. Further details of the criteria and conduct of the statistical analyses will 
be included in the SAP for this study. 
8.5 Efficacy Analysis:  
The primary efficacy variable ORR is the proportion of patients with confirmed Complete 
Response (CR) and Partial Response (PR) recorded from the start of the first dose of poziotinib 
to the end of study and will be analyzed descriptively along with the 95% CI for each cohort. 
The determination of ORR will be based upon an assessment of the local radiological review by 
the respective Principal Investigator using RECIST version 1.1 and/or RANO criteria (for 
GBM). Confirmatory assessments must be completed by the Investigator 4 weeks ± 3 days after the 
first assessment of CR or PR and only confirmed CR/PR can be deemed as CR/PR. 
The secondary endpoints are DCR and DoR, DCR is the proportion of patients with best 
response of CR, PR, and Stable Disease (SD) from the first dose of poziotinib to the end of 
study; and DoR is the time 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.  
Exploratory endpoints are OS and PFS. OS is the time from the treatment start date to the date of 
death during the study and PFS is the time from the treatment start date to the date of 
documented disease progression or death during the study.  
DCR, DoR, OS, and PFS will be analyzed using descriptive statistics, for each cohort, and with 
95% CI for DCR and Kaplan-Meier plot for DoR, OS, and PFS. 
8.6 Safety and Tolerability  
The following variables will be summarized and analyzed descriptively for each cohort: number 
of completed cycles, relative dose intensity, number and percentages of patients with TEAEs, 
SAEs, TEAEs leading to study drug discontinuation, TEAEs related to the study drug; and the 
severity of TEAEs based on CTCAE, Version 5.0.  
8.7 Clinical Laboratory Evaluations 
Key laboratory parameters will be summarized using shift tables, which display a cross-
tabulation of the Baseline grade versus the highest on-study grade for each laboratory parameter, 
for each cohort.  


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All laboratory abnormalities will be classified according to NCI CTCAE, Version 5.0, and 
summarized by worst grade severity and by treatment.  
9 ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT  
9.1 Investigator Responsibilities  
The study will be monitored by employees or representatives of Spectrum. CRAs will monitor 
each site on a periodic basis and perform verification of source documentation for each patient as 
well as other routine compliance reviews. The Sponsor’s Medical Monitor and 
Pharmacovigilance Department will review safety data and be responsible for ensuring timely 
reporting of expedited SAERs to regulatory agencies and Investigators. 
9.1.1 Good Clinical Practice  
It is the responsibility of the Principal Investigator to oversee the safety of the patients at their 
site. The Investigator will ensure that this study is conducted in full compliance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, and with the laws and regulations of the country in which the 
research is conducted as applicable. By signing the US Form FDA 1572, “Statement of 
Investigator”, the Investigator commits to adhere to applicable sections of the US CFR Title 21 
Parts 50 “Protection of Human Patients”, 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, as well as all applicable laws and 
regulations, including US CFR Title 21 Part 54. 
9.1.2 Institutional Review Board/Ethics Committee Approval 
The Investigator shall assure that the IRB/EC will provide an initial and continuing review of the 
study. Prior to screening and enrollment of study patients, documented IRB/EC approval of the 
protocol, ICF and any patient materials must be obtained and provided to Spectrum or its 
designee. 
9.1.3 Informed Consent  
The Investigator is responsible for preparing the written Informed Consent document for this 
study. The Sponsor or its designee will provide the Investigator with an Informed Consent 
template. The Investigator may rearrange or reword the contents of the template, or may add 
other elements or language, provided the meaning and content are not changed or deleted. The 
Sponsor or designee is to review and approve the Informed Consent document that is used by the 
Investigator for this study prior to IRB/EC submission. 
Written Informed Consent will be obtained from all patients participating in this study before any 
procedures are conducted, in accordance with ICH GCP and current regulatory requirements. 
The case history for each patient is to document that the Informed Consent process was obtained 
prior to participation in the study. The original Informed Consent document will be kept in the 
patient’s record, and a copy will be provided to the patient. 


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9.1.4 Study Files and Retention of Records 
The Investigator is to retain all study records until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product as per 21 CFR 312.62 and ICH GCP E6 4.9.5 
and 5.5.12. These documents are to be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility 
of the Sponsor to inform the Investigator when these documents no longer need to be retained. If 
the Investigator relocates, or for any reason desires to dispose of the records, the study records 
may be transferred to another institution, another investigator, or to the Sponsor upon written 
agreement between the Investigator and the Sponsor. 
9.2 Recording and Collecting of Data 
In accordance with ICH and GCP guidelines, the Investigator will maintain complete, accurate, 
legible, and easily retrievable data, and will allow personnel authorized by the Sponsor access to 
all study data at any time. Such data shall also be secured in order to prevent unauthorized access 
to data, or unauthorized editing or loss of data. 
9.2.1 Case Report Forms 
At scheduled monitoring visits, CRFs will be verified against source documentation and 
submitted as final data. Any subsequent changes to the CRFs are to be performed in accordance 
with the Sponsor’s standard operating procedures for editing and clarifying CRFs. Data entry 
will be performed by the sites using an electronic data capture (EDC) system. Comment fields on 
the CRFs will be used as a means of clarification and communication between the Investigator 
and the Sponsor; however, comments entered in these fields will not be edited or clarified. 
9.2.2 Drug Accountability 
In accordance with all applicable regulatory requirements, the Investigator or designated site 
staff is to maintain study treatment accountability records throughout the course of the study. 
This person(s) will document the amount of poziotinib administered to patients. The CRA will 
review inventory and accountability documentation during monitoring visits. 
The Investigator will not supply investigational study drugs to other investigators not listed on 
the US Form FDA 1572 or equivalent. Investigational study drug use, other than as directed by 
this protocol, is not allowed. 
All unused vials of poziotinib are to be accounted for at the site and maintained in a secured, 
locked storage area with access limited to authorized study personnel only. Used poziotinib 
vials/bottles will be destroyed per institution, local, and all applicable policies and procedures. 
After study conclusion, all unused vials of poziotinib may be destroyed at the site, following 
verification of accountability by a Spectrum representative. 
9.3 Protocol Compliance 
The Principal Investigator is responsible for ensuring the study is conducted in accordance with 
the procedures and evaluations described in this protocol. 


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9.4 Sponsor Responsibilities 
9.4.1 Safety Monitoring 
The clinical drug safety of study treatment will be continuously evaluated by the study Medical 
Monitor or designee on an ongoing basis during the course of this clinical study. All SAEs 
related to study treatment in this study and all other ongoing clinical studies with study treatment 
will be processed in compliance with current regulatory guidelines by the Sponsor’s 
Pharmacovigilance Department. This processing will include a formal assessment of each SAE 
by drug safety. In addition, a cumulative review of all SAEs from all sources will be assessed 
periodically.  
9.5 Joint Investigator/Sponsor Responsibilities 
9.5.1 Access to Information for Monitoring and Auditing 
In accordance with ICH GCP guidelines and 21 CFR 312, the CRA/auditor is to have direct 
access to the patient’s source documentation in order to verify the data recorded in the CRFs. 
The CRA is responsible for routine review of the CRFs at regular intervals throughout the study 
and to verify adherence to the protocol, as well as the completeness, consistency, and accuracy of 
the data being recorded. The CRA/auditor is to have access to any patient records needed to 
verify the entries on the CRFs, as well as access to all other study-related documentation and 
materials. The Investigator agrees to provide the monitor with sufficient time and facilities to 
conduct monitoring, and to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring/auditing visits are resolved. 
9.5.2 Termination of the Study 
For reasonable cause, either the Investigator or 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, as per the terms mentioned in the CTA, 
the Sponsor may terminate the study at any time upon immediate notice for any reason, including 
but not limited to, Spectrum’s belief that termination is necessary for the safety of patients. 
9.5.3 Publication Policy 
To coordinate the dissemination of data from this study, the Sponsor encourages the formation of 
a publication committee consisting of the principal investigator and appropriate Spectrum staff. 
The committee is expected to solicit input and assistance from other investigators and Sponsor 
staff as appropriate. Membership on the committee (both for investigators and Sponsor staff) 
does not guarantee authorship – the criteria described below should be met for every publication. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirements for Manuscript Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors, 2005), which states: 
• Authorship credit should be based on the following; authors should meet all three 
conditions:  
 Substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data 
 Drafting the article or revising it critically for important intellectual content  


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 Final approval of the version to be published  
• When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript. These individuals should 
fully meet the criteria for authorship defined above.  
• Acquisition of funding, collection of data, or general supervision of the research group 
alone does not constitute authorship. 
• All persons designated as authors should qualify for authorship, and all those who qualify 
should be listed. 
• Each author should have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
• All publications (e.g., manuscripts, abstracts, oral/slide presentations, books chapters) 
based on this study must be submitted to the Sponsor for corporate review. 
9.6 Confidentiality 
All information provided to the Investigator by the Sponsor, including nonclinical data, 
protocols, CRFs, information regarding poziotinib, 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 the relevant CTA with Sponsor, 
including related to the confidentiality provisions and any right of publication granted to the 
Investigator in the CTA. All personnel will handle patient data in a confidential manner in 
accordance with applicable regulations governing clinical research and in accordance with the 
CTA. Upon request by a regulatory authority such as the US FDA and other regulatory 
authorities worldwide, the Investigator/institution is to make available for direct access all 
requested study-related records or reports generated as a result of a patient’s participation in this 
study in accordance with the procedures and requirements of the CTA. 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 and subject to the confidentiality and other provisions of 
the CTA. 
 


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65 
10 REFERENCES 
1. 
Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in 
cancer. Nature medicine. 2013;19(11):1389-400. 
2. 
Scholl S, Beuzeboc P, Pouillart P. Targeting HER2 in other tumor types. Annals of 
oncology : official journal of the European Society for Medical Oncology / ESMO. 
2001;12 Suppl 1:S81-7. 
3. 
Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase 
inhibition in patients with HER2- and HER3-mutant cancers. Nature. 
2018;554(7691):189-94. 
4. 
Yang JC-H, Sequist L, O'Byrne K, Schuler M, Mok T, Geater S, et al. Epidermal growth 
factor receptor (EGFR)-mediated adverse events (AEs) in patients (pts) with EGFR 
mutation positive (EGFR M+) non-small cell lung cancer treated with afatinib. European 
Journal of Cancer. 2013;49:S190. 
5. 
Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and 
clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small 
cell lung cancer. Nature medicine. 2018;24(5):638-46. 
6. 
Heymach JV, Negrao MV, Robichaux JP, Carter BW, Patel A, Altan M, et al. A Phase II 
Trial of Poziotinib in EGFR and Her2 Exon 20 Mutant Non-Small Cell Lung Cancer 
(NSCLC).  IASLC 19th World Conference on Lung Cancer; Toronto, Canada2018. p. 
OAO2.06. 
7. 
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape 
of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. 
Nature medicine. 2017;23(6):703-13. 
8. 
Priestley P, Baber J, Lolkema M, Steeghs N, de Bruijn E, Duyvesteyn K, et al. Pan-
cancer whole genome analyses of metastatic solid tumors. bioRxiv. 2018. 
9. 
Robichaux JP, Tan Z, Elamin YY, Zhang S, Liu S, Li S, et al. Identification of molecular 
features of kinase inhibitors that circumvent steric hindrance induced by exon 20 
insertions in EGFR and HER2 mutant NSCLC. 2017. 
10. 
Robichaux J, Nilsson, MB, He, J, Hu, L, Zhang, F, Pisegna, M, Poteete, A, and Heymach 
JV, editor Identification of poziotinib alone or in combination with T-DM1 as a pan-
HER2 inhibitor. AACR; 2019; Atlanta, GA. 
11. 
Robichaux JP, Elamin YY, Tan Z, Carter BW, Zhang S, Liu S, et al. Mechanisms and 
clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small 
cell lung cancer. Nature medicine. 2018;24(5):638-46. 
12. 
Noh YH, Lim HS, Jung JA, Song TH, Bae KS. Population pharmacokinetics of HM781-
36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in 
patients with advanced solid malignancies. Cancer chemotherapy and pharmacology. 
2015;75(1):97-109. 
13. 
Pandey A, Brufsky AM. Metastatic Breast Cancer Patient With Activating 
<em>HER2</em> Exon 20 Insertion Mutation With Response to Poziotinib: Case Report 
of Compassionate Drug Use. Clinical breast cancer. 2018. 


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14. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
European journal of cancer (Oxford, England : 1990). 2009;45(2):228-47. 
15. 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. 
Updated response assessment criteria for high-grade gliomas: response assessment in 
neuro-oncology working group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2010;28(11):1963-72. 




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e) 
Pregnancy test (β-HCG) in women of child-bearing potential.  Blood pregnancy test is required at Screening. Urine pregnancy test is required on Day 1 of each Cycle starting from Cycle 2 and at 
Cycle 1, Day 1, if Screening pregnancy test was more than 7 days prior to Day 1. Urine pregnancy test also required at End-of-Treatment Visit. 
f) 
The Screening tumor assessment for patient eligibility will be based on scans performed within 30 days before the patient signed the ICF. Either CT, PET/CT, or MRI scans should be performed for 
non-brain organs and brain MRI scans should be performed locally per standard of care before the patient signed the ICF. Baseline tumor assessment (CT, PET/CT or MRI for non-brain and brain 
MRI) will be performed within 14 days prior to Cycle 1, Day 1 and additional assessments will be made at 4 weeks (Cycle 2, Day 1 [up to Cycle 2, Day 7]), at 8 weeks (Cycle 3, Day 1 [up to Cycle 
3, Day 7, with at least 28 days from previous tumor assessment]), and then every 8 weeks (±7 days) thereafter until disease progression, death, intolerable adverse events (AEs), or other protocol-
specified reasons for patient withdrawal. 
g) 
Tumor histopathology report (from local pathologist) and molecular test report for mutation diagnosis. 
h) 
Complete blood count (CBC), including white blood cells with 5-part differential, hemoglobin, and platelets, is to be obtained within 7 days prior to poziotinib administration on Day 1 of each cycle, 
at which time, the patient’s absolute neutrophil count ≥1.0×109/L and platelet count ≥75 ×109/L before administering the next dose of poziotinib. In addition, a CBC is to be performed on Day 8 of 
Cycles 1 and 2. 
i) 
Blood for chemistry is to be collected within 7 days prior to poziotinib administration on Day 1 of each Cycle. 
j) 
ECGs will be performed at screening. At select study centers, up to 25 patients may be specifically consented for ECG as defined below:  
Schedule:  A local 12-lead ECG will be obtained just before each PK blood sample on both Day 1 and Day 8. If the patient has interrupted continuous poziotinib dosing, clear 
dosing documentation must be done in order to assess suitability of further PK sampling and ECG recording.  
k) 
Cardiac ejection fraction may be evaluated at Screening in patients who are considered at high risk of cardiac disease, as determined by the Investigator, using echocardiogram or multi-gated 
acquisition (MUGA) scan. The investigator can order subsequent tests based on patient standard of care as determined by the Investigator.  
l) 
Tumor genotyping report from local lab is required to confirm patient mutation eligibility. Tissue sample (archival or fresh biopsy), if available, should be retained for retrospective analysis by 
FoundationOne CDx test. Collecting a tissue sample at progression is optional but is highly encouraged.  
m) Plasma samples will be required at Screening and optional on the day of each on-study imaging session, beginning at the 4-week imaging session, once every 8 weeks with imaging scan and when 
the patient progresses for biomarker analysis. Guardant’s 360 or FoundationACT assays will be used, Plasma sample collection and storage will follow vendors’ standard procedures as described in 
the vendors’ Laboratory Manual. 
n) 
Whole blood samples will be drawn at Screening for pharmacogenomic analysis.  
o) At select study centers, up to 25 patients may be specifically consented for intensive PK sampling as defined below:  
Schedule:  Intensive PK blood sampling will be at pre-dose and 2, 4, 8, 12, and 24 hours post-dose on Cycle 1, Day 1 and on Cycle 1, Day 8 (±3 days). The 12-hour and 24-hour 
PK samples must be collected prior to the second daily dose. If the patient has interrupted continuous poziotinib dosing, clear dosing documentation must be done in order to 
assess suitability of further PK sampling and ECG recording. In addition, if a patient presents with a potentially drug-related Grade ≥3 AE, a PK sample should be collected as 
soon as possible, if feasible, following the onset of the AE in order to characterize the PK. Documentation of last dose timing prior to the event is required.  
p) 
Poziotinib and loperamide will be dispensed on Day 1 of each cycle. Patients will take poziotinib orally twice daily with food and a glass of water at approximately the same times each day. 
Loperamide will be given prophylactically for diarrhea as follows: 4 mg twice daily (bid) to three times daily (tid or according to treating physician’s instruction. .  
q) 
Adverse events will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) and during Screening only study-related SAEs to be 
recorded. 
r) 
Weekly calls to patients will be conducted during the Days 3 to 8 of each cycle for the first 2 cycles as a follow up of expected adverse events.  
s) 
Patients who have consented will be contacted by phone (or email or letter if specifically requested) every 3 months, for up to 2 years after patient’s first dose of poziotinib, for survival assessment. 
 
 
 






Spectrum Pharmaceuticals, Inc. 
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Protocol Number: SPI-POZ-203 
Amendment 1: 20 May 2021 
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Severe Diarrhea 
*(CTCAE Grade 3) 
- 
Continue Loperamide 4 mg orally, 3 times a day, followed by 2 
mg every 4 hours or after each loose stool  
- 
Continue Doxycycline at 100 mg orally (or alternatively use 
Minocycline 100 mg orally) twice a day, continue for 2 weeks or 
until resolution of diarrhea 
- 
If started then continue Cholestyramine OR Budesonide (if 
started) 
- 
Consider Octreotide SubQ: 100 to 150 mcg every 8 hours; may 
increase to 500 to 1500 mcg IV or SubQ every 8 hours 
- 
Hold Poziotinib for one week and restart at the lower dose  
- 
Upon resolution or diarrhea improvement to ≤ Grade 1, 
Poziotinib dose escalation may be allowed after approval from 
the Sponsor 
 
Increase of >=7 stools 
per day over baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self-
care ADL 
 
 
Gastrointestinal 
disorders 
*GRADE 
Adverse Event 
1 
2 
3 
4 
5 
Diarrhea 
Increase of 
<4 stools 
per day over 
baseline; 
mild 
increase in 
ostomy 
output 
compared to 
baseline 
 
Increase of 4 - 6 
stools per day 
over baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline; 
limiting 
instrumental 
ADL 
 
Increase of >=7 
stools per day 
over baseline; 
hospitalization 
indicated; severe 
increase in 
ostomy output 
compared to 
baseline; limiting 
self-care ADL 
 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Death 
Definition of Diarrhea: A disorder characterized by an increase in frequency and/or watery bowel movements. 
 
** The maximum daily dose of Loperamide is 16 mg  
 
Version 1,  
Dec, 12. 2017 


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RASH MANAGEMENT RECOMMENDATIONS  
RECOMMENDATIONS FOR ACNEIFORM RASH MANAGEMENT  
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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Spectrum Pharmaceuticals, Inc. 
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Amendment 1: 20 May 2021 
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Operative intervention 
indicated; IV 
antibiotics indicated; 
limiting self-care ADL 
• 
Consider partial or total nail avulsion if ingrown nail is visible. 
• 
Oral or IV antibiotics as per wound culture sensitivity 
• 
Hold Poziotinib 
• 
Continue all CTCAE recommendations unless otherwise stated 
*CTCAE Severity 
Grading of paronychia: 
 
Infections and 
Infestations 
 
 
 
 
GRADE 
 
Adverse Event 
1 
2 
3 
4 
5 
Paronychia 
Nail fold edema 
or erythema; 
disruption of the 
cuticle 
Local intervention 
indicated; oral intervention 
indicated (e.g., antibiotic, 
antifungal, antiviral); nail 
fold edema or erythema 
with pain; associated with 
discharge or nail plate 
separation; limiting 
instrumental ADL 
Operative 
intervention 
indicated; IV 
antibiotics 
indicated; 
limiting self-
care ADL 
- 
- 
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail. 
*CTCAE v5.0 
Vinegar soaks: 1 part water to 1 part vinegar: soak 15 minutes daily 
Dilute bleach soaks: 1 tablespoon bleach to 1 gallon water: soak 15 minutes daily 
 
References: 
Lacouture, ME et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated 
dermatologic toxicities. Support Care Cancer (2011) 19:1079–1095. 
Melosky, B et al. Management of egfr tki–induced dermatologic adverse events. Curr Oncol (2015) 22:123-
132. 
Version 1, Aug 2018