Phase 2 Study of Poziotinib in Patients With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multi-center study to evaluate the efficacy and the safety/tolerability of poziotinib in seven patient cohorts for up to 603 previously treated and treatment-naïve NSCLC patients. Cohorts 3 and 4 were added with Amendment 1 and three additional cohorts were added with Amendment 2 (Cohorts 5, 6 and 7).

Detailed Description
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The Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, Day 1. Patients must meet all Inclusion/Exclusion Criteria to participate in the study. Eligible patients will provide written Informed Consent prior to undergoing any study procedures. Each treatment cycle is 28 calendar days in duration. There will be seven patient cohorts and eligible patients will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status: Cohort 1: Previously treated patients with EGFR exon 20 insertion mutation positive NSCLC (complete) Cohort 2: Previously treated patients with HER2 exon 20 insertion mutation positive NSCLC (complete) Cohort 3: Treatment naïve patients with EGFR exon 20 insertion mutation positive NSCLC (complete) Cohort 4: Treatment naïve patients with HER2 exon 20 insertion mutation positive NSCLC (fully enrolled) Cohort 5: Patients who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed (closed to enrollment) Cohort 6: Patients with acquired EGFR mutation who progressed while on treatment with first-line osimertinib (closed to enrollment) Cohort 7: Patients with EGFR or HER2 activating mutations (closed to enrollment) Toxicity will be assessed based on the grade of the adverse events using CTCAE version 4.03. On Day 1 of each 28-day cycle, the patient's absolute neutrophil count (ANC) must be ≥1.5×10^9/L and platelet count must be ≥100×10^9/L before administering poziotinib. All patients will be treated until disease progression (except for first progression in Cohort 5), death, intolerable adverse events (AEs), or other protocol-specified reasons for patient withdrawal.

Official Title
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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)

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Poziotinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements 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 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 Cohorts 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 Specific mutations: Cohort 1 and 3: Documented EGFR exon 20 insertion mutation Cohort 2 and 4: Documented HER2 exon 20 insertion mutation Cohort 5: Documented EGFR or HER2 exon 20 insertion mutations Cohort 6: Documented acquired EGFR mutation (tested after osimertinib progression) Cohort 7: Documented EGFR or HER2 activating mutations Patient has adequate organ function at Baseline Key Exclusion Criteria: 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). 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 half lives, whichever is longer; local radiation therapy for bone pain may be allowed 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 Patient is pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Each treatment cycle is 28 calendar days in duration. There will be seven patient cohorts and eligible patients will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status: Cohort 1: Previously treated patients with EGFR exon 20 insertion mutant positive NSCLC (closed to enrollment) Cohort 2: Previously treated patients with HER2 exon 20 insertion mutant positive NSCLC (closed to enrollment) Cohort 3: Treatment naïve patients with EGFR exon 20 insertion mutant positive NSCLC (fully enrolled) Cohort 4: Treatment naïve patients with HER2 exon 20 insertion mutant positive NSCLC 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 acquired EGFR mutation who progressed while on treatment with first-line osimertinib Cohort 7: Patients with EGFR or HER2 activating mutations
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Poziotinib<br>Cohort 1: Previously treated patients with EGFR exon 20 insertion mutant positive NSCLC (closed to enrollment) Cohort 2: Previously treated patients with HER2 exon 20 insertion mutant positive NSCLC (closed to enrollment) Cohort 3: Treatment naïve patients with EGFR exon 20 insertion-mutant positive NSCLC (fully enrolled) Cohort 4: Treatment naïve patients with HER2 exon 20 insertion mutant positive NSCLC 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 acquired EGFR mutation who progressed while on treatment with first-line osimertinib Cohort 7: Patients with EGFR or HER2 activating mutations | Drug: Poziotinib<br>* The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration. Cohorts 1-3: 16 mg QD Cohort 4: 8 mg BID Cohort 5: randomized to 8 mg BID or 6 mg BID or 10 mg QD Cohorts 6 and 7: 8 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The proportion of subjects who achieve Complete Response (CR) and Partial Response (PR) by the best response from the first dose of poziotinib to the end of study. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | The proportion of subjects who achieve CR, PR, and Stable Disease (SD) by the best response from the first dose of poziotinib to the end of study. | 24 months | 
| Duration of Response (DoR) | Number of days 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. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, HER2, Exon 20 insertion mutation