Study of Poziotinib in Japanese Patients With NSCLC

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

Detailed Description
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This is a Phase 1/2, open-label, multicenter study in Japanese patients with locally advanced or metastatic NSCLC. This study will be conducted in two parts. Phase 1 is designed to observe the maximum tolerated dose (MTD) or maximum administered dose (MAD) of poziotinib when administered once daily or twice daily. Phase 2 will evaluate the safety and efficacy of the dose determined in Phase 1. Study participation includes a 30 day screening period, up to 24 months of treatment, and long-term follow-up for a maximum of 24 months after discontinuation of study treatment. Phase 1 will enroll up to 36 patients into a dose finding study with two parallel, randomized dose groups. Each group will undergo a dose-finding scheme using a 3+3 design with the assessment of dose-limiting toxicities (DLTs) at up to three dose levels. Patients will be randomized into once daily (QD) or twice daily (BID) dose groups. The DLT assessment will be conducted in the first cycle of treatment and therefore, poziotinib dose modifications are not permitted during this cycle. Patients will be hospitalized for the first 2 weeks. Phase 2 will enroll 40 additional NSCLC patients with EGFR (20 patients) or HER2 (20 patients) exon 20 insertion mutations. Efficacy and safety of the dose and dosing regimen determined in Phase 1 will be evaluated. All patients will be treated in 28-day cycles for up to 24 months.

Official Title
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A Phase 1/2 Dose Finding Study of Poziotinib in Japanese Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Poziotinib Once Daily Dosing
* Drug: Poziotinib Twice Daily Dosing
* Drug: Poziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1


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 Previously treated patient with histologically or cytologically confirmed (archival tissue accepted) locally advanced or metastatic non-small cell lung cancer (NSCLC) and is not a candidate for definitive therapy Phase 1: No test for mutational status is required Phase 2: Documented EGFR or HER2 exon 20 insertion mutations (including duplication mutations) in NSCLC patients Prior treatment status: Phase 1: Patient with refractory NSCLC to available standard therapies Phase 2: Progression after at least one systemic therapy for locally advanced or metastatic disease Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Metastatic lesions in bone, CNS, or in brain cannot be used for target lesions. 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 Key Exclusion Criteria: Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks prior to Cycle 1, Day 1; local radiation therapy for bone pain may be allowed Patient has used strong inhibitors/inducers of CYP3A4 and CYP2D6 within 1 month prior to Cycle 1, Day 1 Patient has had another primary malignancy within 3 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ Patient is pregnant or breastfeeding Phase 2 : Patient has had previous treatment with poziotinib. The currently approved TKIs that are not considered to be exon 20 insertion-selective are permissible

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1 will have two randomized, parallel dose groups comparing daily dosing and twice daily dosing at 3 dose levels. Phase 2 will be a single dose group evaluating the safety and efficacy of the dose determined in Phase 1 in 2 Cohorts. Cohort 1: EGFR exon 20 insertion mutations and Cohort 2: HER2 exon 20 insertion mutations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Once Daily Dosing<br>Dose finding at 8 mg, 12 mg, or 16 mg of poziotinib once daily in 28-day treatment cycles. | Drug: Poziotinib Once Daily Dosing<br>* The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.<br>|
| Experimental: Phase 1: Twice Daily Dosing<br>Dose finding at 4 mg, 6 mg, or 8 mg of poziotinib twice daily in 28-day treatment cycles. | Drug: Poziotinib Twice Daily Dosing<br>* The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.<br>|
| Experimental: Phase 2: Once Daily Dosing or Twice Daily Dosing<br>Once Daily or Twice Daily Dosing as determined in Phase 1 in 28-day treatment cycles. Cohort 1: EGFR exon 20 insertion mutations Cohort 2: HER2 exon 20 insertion mutations | Drug: Poziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1<br>* The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) | MTD/MAD will be assessed based on the occurrence of defined dose-limiting toxicities (DLT) and all available safety information during first cycle of treatment. | 28 Days | 
| Phase 2: Objective Response Rate (ORR) | The proportion of patients who achieve Complete Response (CR) or Partial response (PR) by the best response from the first dose of poziotinib to the end of the study. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Disease Control Rate (DCR) | The proportion of patients who achieve CR, PR, and Stable Disease (SD) by the best response from the first dose of poziotinib to the end of the study. | 24 months | 
| Phase 2: Duration of Response (DoR) | The 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 | 
| Phase 2: Progression Free Survival (PFS) | The number of days from the treatment start date to the date of documented disease progression or death. | 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