A Phase 2 Study of Poziotinib in Patients with Non-Small Cell Lung Cancer (NSCLC),
Locally Advanced or Metastatic, with EGFR or HER2 Exon 20 Insertion Mutation (ZENITH20)

1. Patient is at least 18 years of age
2. Patient must be willing and capable of giving written Informed
Consent, adhering to dosing and visit schedules, and meeting all study
requirements
3. Patient has histologically or cytologically confirmed locally advanced
or metastatic non-small cell lung cancer (NSCLC) that is not amenable to
treatment with curative intent
4. Prior treatment status:
• Cohorts 1 and 2: Patient has had at least one prior systemic treatment for
locally advanced or metastatic NSCLC
• Cohorts 3 and 4: Patient is treatment-naïve for locally advanced or
metastatic NSCLC and eligible to receive first-line treatment with poziotinib
as determined by the Investigator. Adjuvant/neo-adjuvant therapies
(chemotherapy, radiotherapy, or investigational agents) are permissible as long
as they end at least 15 days prior to study entry.
• Cohort 5: Patients who meet the criteria for enrollment in Cohort 1 to 4, but
the enrollment in the respective cohort has been closed • Cohort 6: Patients
with EGFR mutation-positive NSCLC who progressed while on treatment with
first-line osimertinib. • Cohort 7: Patient has had at least one prior systemic
treatment for locally advanced or metastatic NSCLC
5. Tissue and plasma samples for mutation confirmation: • Cohorts 1 to 5:
Patient has adequate tumor tissue obtained from a biopsy or surgical procedure
to enable molecular profiling for retrospective central laboratory confirmation
of the mutation. If tissue is not available, the patient must have biopsy
accessible disease and must be willing to undergo a biopsy to provide an
appropriate tissue sample prior to receiving treatment in the study. • Cohort
6: Either tissue or plasma samples after osimertinib progression. • Cohort 7:
Either tissue or plasma samples.
6. Patient is positive for EGFR or HER2 exon 20 mutations based on tissue
testing:
• Cohorts 1 and 3: Documented EGFR exon 20 insertion mutation
(including duplication mutations) using a next generation sequencing diagnostic
test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, or by
an FDA approved test (eg, cobas® EGFR mutation test v2 or therascreen EGFR RGQ
PCR kit) performed by a US CLIA certified and locally licensed clinical
laboratory or similarly accredited lab for ex-US sites using tissue samples
• Cohorts 2 and 4: Documented HER2 exon 20 insertion mutation
(including duplication mutations) using a next generation sequencing diagnostic
test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay,
performed by a US CLIA certified and locally licensed clinical laboratory or
similarly accredited lab for ex-US sites using tissue samples
• Cohort 6: Documented acquired EGFR mutation (tested after osimertinib
progression) who have progressed while on first-line osimertinib treatment
using tissue or plasma tested with a next generation sequencing assay. • Cohort
7: Documented EGFR or HER2 activating mutations using tissue or plasma tested
with a next-generation sequencing assay.
7. Patient has measurable NSCLC disease, as per the Response Evaluation
Criteria in Solid Tumors (RECIST, version 1.1). (Text removed).
8. Brain metastases may be allowed if patient's condition is stable,
defined as clinically asymptomatic, no requirement for high dose or increasing
dose of systemic corticosteroids, and no need for any anticonvulsant therapy
for metastatic brain disease. For the patient who has had radiation therapy,
sequential post-treatment MRI tests, at least
4-6 weeks apart, should show no increases in brain lesion size/volume within 4
weeks prior to the study.
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status
0 or 1 and has a life-expectancy of more than 6 months
10. Patient has recovered from prior systemic therapy for metastatic disease to
Grade <=1 for non-hematologic toxicities (except for Grade <=2 peripheral
neuropathy) and has adequate hematologic, hepatic, and renal function at
Baseline, as defined by:
• Leukocytes >=3.0×10 9/L
• Absolute neutrophil count (ANC) must be >=1.5×10 9/L
• Platelet count >=100×10 9/L
• Hemoglobin >=9.0 g/dL
• Total bilirubin <=2 mg/dL; if hepatic metastases are present, <=2.5×ULN
• SGOT (AST) and SGPT (ALT) <=2.5×ULN with the following exception;
Patients with liver metastases AST, ALT <=5×ULN
• Creatinine clearance >=50 mL/min
11. Patient is willing to practice 2 forms of contraception, one of which must
be a barrier method, from study entry until at least 30 days after the last
dose of poziotinib
12. Females of childbearing potential must have a negative pregnancy test
within 7 days prior to Day 1. Females who are postmenopausal for at least 1
year (defined as more than 12 months
since last menses) or who are surgically sterilized do not require this test.

1. Patient has:
• All Cohorts: EGFR T790M
• Cohorts 1 to 5: EGFR exon 20 point mutation
• Cohort 7: EGFR Exon 19 deletion and L858R or HER2 T798I mutations, EGFR and
HER2 Exon 20 insertion mutation
2. Patient has had previous treatment with poziotinib or any other EGFR or HER2
exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to
study participation. The currently approved TKIs (ie, erlotinib, gefitinib,
afatinib, osimertinib) are not considered to be exon
20 insertion-selective and are permissible (Cohorts 1 and 2).
3. Patient is concurrently receiving chemotherapy, biologics, immunotherapy
for cancer treatment; systemic anti-cancer treatment or investigational
treatment should not be used within 2 weeks or 5 halflives, whichever is
longer; local radiation therapy for bone pain may be allowed.
4. Patient has a history of congestive heart failure (CHF) Class III/IV
according to the New York Heart Association (NYHA) Functional Classification or
serious cardiac arrhythmias requiring treatment
5. Patient has a high risk of cardiac disease, as determined by the
Investigator, may undergo either echocardiogram (ECHO) or multi-gated
acquisition (MUGA) during Screening and has a cardiac ejection fraction <50%.
6. Patient has had other malignancies within the past 3 years, except for
stable non-melanoma skin cancer, fully treated and stable early stage prostate
cancer or carcinoma in situ of the cervix or breast without need of treatment
7. Patient is confirmed to have clinically significant or recent acute
gastrointestinal disease presenting as diarrhea and/or coloenteritis as a main
symptom (ie, acute enteritis, malabsorption, or Common Terminology Criteria for
Adverse Events (CTCAE, version 4.03) Grade 2 or above diarrhea due to other
etiologies)
8. Patient has an active Grade >=2 skin disorder, rash, mucositis, or skin
infection that needs medication or therapy or existing Grade >=2 skin toxicity
from previous therapies; Grade >=2 neuropathy, Grade >=2 pneumonitis.
9. Patient is unable to take drugs orally due to disorders or diseases that may
affect gastrointestinal function, such as inflammatory bowel diseases (eg,
Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures
that may affect gastrointestinal function, such
as gastrectomy, enterectomy, or colectomy
10. Patient has an active liver disease or biliary tract disease (except for
Gilbert's disease, asymptomatic biliary stones, liver metastasis, or stabilized
chronic liver diseases)
11. Patient has known hypersensitivity to poziotinib or has a history of
allergic reactions attributed to chemically similar compounds or other tyrosine
kinase inhibitors (TKIs)
12. Patient has an active uncontrolled infection, underlying medical condition,
or other serious illness that would not be appropriate for this study
13. Patient has unstable, uncontrolled, active bleeding disorders that the
investigator considers that the patient could be at increased risk or not be
suitable for treatment in this study
14. Patient is pregnant or breast-feeding.
15. Cohort 5 only: Patient is eligible for treatment in an open cohort (Cohorts
1 to 4).