A Study of ZN-e4 in Subjects With Epidermal Growth Factor Receptor Mutated Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2, open-label, multicenter, sequential dose-escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ZN-e4 administered orally in subjects with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations who have progressed while on treatment with an EGFR tyrosine kinase inhibitor (TKI) agent (other lines of treatment are allowed, except for other epidermal growth factor receptor inhibitors [EGFRis]) for Phase 1; and for Phase 2, subjects who have T790M+ and are osimertinib naïve (Cohort 1), and also those who have not been treated with an EGFR Inhibitor (EGFRi) (Cohort2).

Official Title
-----------------
A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of ZN-e4 (KP-673) in Patients With Advanced Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor (EGFR) Mutations

Conditions
-----------------
Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
-----------------
* Drug: ZN-e4


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA Age ≥ 18 years Histologically or cytologically confirmed metastatic or advanced inoperable diagnosis of NSCLC Documented radiographic progression on the last treatment administered prior to enrolling in the study. Phase 1 only: Confirmation that the tumor harbors an EGFR mutation known to be associated with aberrations that are amenable to EGFRi therapy including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q. OR - Must have experienced clinical benefit from an EGFRi, All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 or baseline before the start of study drug dosing (with the exception of alopecia [any grade permitted] and neurotoxicity [Grade 1 or 2 permitted]). Measurable disease meeting the criteria specified by RECIST v1.1 Phase 2, Cohort 1 only: Subjects must have confirmation of tumor T790M mutation status (confirmed positive) and are osimertinib naïve Phase 2, Cohort 2 only: EGFR aberrations that are amenable to EGFRi therapy, including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q, and be EGFRi naïve EXCLUSION CRITERIA Subjects who have received only neoadjuvant or adjuvant therapy for NSCLC. Phase 1 only: Treatment with an EGFRi within 7 days or 5 half-lives of the first dose of study treatment, whichever is shorter. Phase 1 only: Cytotoxic chemotherapy, investigational agents, or any anticancer therapy for the treatment of advanced NSCLC (other than EGFRi) within 21 days of the first dose of study treatment. Prior treatment with immunotherapy within 3 months prior to the first dose of study treatment. Radiotherapy within 28 days of first dose of study treatment; subjects given palliative radiotherapy to peripheral sites (e.g., bone metastases) may enter the study before 28 days have elapsed provided the radiated sites do not contain lesions which may be used to evaluate response, and must have recovered from any acute, reversible effects. Known or suspected central nervous system (CNS) metastases or leptomeningeal disease (Phase 1 only). Subjects with previously treated brain or CNS metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy, does not have brain metastasis related symptoms, is not requiring systemic steroids for at least 2 weeks prior to study drug administration, and any whole brain radiation therapy was completed at least 4 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) was completed at least 2 weeks prior to study drug administration. Prior allogeneic bone marrow transplantation. History of a concurrent or second malignancy except for: adequately treated local basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; breast carcinoma in situ; adequately treated Stage 1 or 2 cancer currently in complete remission; any other cancer that has been in complete remission for ≥5 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Up to 9 sequential dose escalation cohorts to determine maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is identified. | Drug: ZN-e4<br>* Oral dose, tablet, daily dosing<br>|
| Experimental: Phase 2<br>MTD/RP2D in subjects: Cohort 1: with T790M mutation in epidermal growth factor receptor (EGFR) gene, and are osimertinib naïve. Cohort 2: EGFRm amenable to EGFR inhibitor therapy (eg, exon 19 del, L858R) and who have never been treated with EGFRis. | Drug: ZN-e4<br>* Oral dose, tablet, daily dosing<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed dose limiting toxicities |  | 1 Cycle (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as measured by incidence of treatment emergent adverse events |  | Through study completion, approximately 2 years |