A Study to Investigate Safety, Tolerability, PK and Anti-tumor Activity of TRX-221 in EGFRm NSCLC Patients

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2, open-label study designed to investigate the safety, tolerability, PK, and anti-tumor activity of the study treatment in the treatment of patients with EGFR mutant NSCLC, who progressed following prior standard treatments which include the approved EGFR-TKIs with activity against T790M (e.g., osimertinib).

Detailed Description
-----------------
All eligible patients will receive the study treatment at selected oral dose(s) once daily. Patients will be treated continuously until disease progression or any other pre-defined discontinuation criteria are met.

Official Title
-----------------
An Open Label, Multicenter, Phase 1/2 Study to Explore the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of TRX-221 in the Treatment of Patients With EGFR Mutant NSCLC Who Progressed Following Prior Therapy With EGFR TKI

Conditions
-----------------
Carcinoma, Non-Small-Cell Lung, EGFR Mutant Advanced Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: TRX-221


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with ECOG performance status score of 0 or 1 Histologically or cytologically confirmed diagnosis of relapsed or refractory, locally unresectable advanced or metastatic NSCLC harboring an activating EGFR mutation Failed standard of care treatments progressed after anti tumor treatments including at least 1 approved EGFR TKI [Phase2: TKIs should include the approved EGFR TKIs with activity against T790M (e.g., osimertinib)] Slots may be reserved for patients with certain resistant mutations (i.e., EGFR C797X mutation with or without T790M mutation as required by the sponsor) [Phase 1] EGFR C797X mutation with or without T790M mutation [Phase 2] Not received more than 1 prior line of platinum based chemotherapy in the metastatic setting [Phase 2] Having at least 1 measurable tumor lesion per RECIST v1.1 criteria [Phase 2] Having adequate bone marrow, hepatic, and renal function as specified in the protocol Exclusion Criteria: NSCLC with mixed cell histology or a tumor with histologic transformation of small cell elements Patients having tumor with any additional known driver of alterations Patients with presence of another active primary malignant tumor that has been diagnosed or required therapy within 2 years prior to the initiation of the study treatment Patients who have unstable and symptomatic primary CNS tumors/metastasis, leptomeningeal metastases or spinal cord compression which are not suitable for enrollment, as judged by the Investigator Patients having clinically active ongoing ILD of any etiology Clinically significant cardiac conditions, infections, refractory GI diseases as specified in the protocol Patients having any unresolved toxicities from prior anti tumor therapy and surgery greater than CTCAE Grade 1 at the time of starting the study treatment Recent anticancer therapy: EGFR-TKI, Immunotherapy or any other systemic anticancer therapy or radiotherapy (specific duration prior to starting study medication per protocol)

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Part A: Dose escalation in patients with EGFR sensitizing mutation<br>All eligible patients will receive the study treatment at selected oral dose(s) once daily, as per the assigned dose level from the pre-defined escalation scheme and SRC(Safety Review Committee) decision. | Drug: TRX-221<br>* TRX-221 oral dose as defined<br>|
| Experimental: Phase 1 Part B: 2 dose levels of TRX-221 in patients with EGFR sensitizing mutation<br>All eligible patients will receive the study treatment at selected oral dose(s) once daily. Dose-levels will be selected from the Part A. | Drug: TRX-221<br>* TRX-221 oral dose as defined<br>|
| Experimental: Phase 2: Recommended Phase 2 dose(s) of TRX-221 in patients with EGFR C797X mutation<br>All eligible patients will receive the study treatment at selected oral dose(s) once daily. | Drug: TRX-221<br>* TRX-221 oral dose as defined<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [Phase1 PartA: Dose Escalation] To assess the safety/tolerability and determine the MTD/RP2D range of TRX-221 | Incidence and severity of AEs graded according to the NCI-CTCAE v5.0 Number and percentage of patients with TEAEs, SAEs, and DLTs Safety and tolerability as noted by laboratory data, vital signs, physical examinations, and 12-lead ECGs | Approx. 12 months | 
| [Phase1 PartB: Dose Exploration] To determine the RP2D of TRX-221 | Incidence and severity of AEs, TEAEs, SAEs Safety and tolerability as noted by laboratory data, vital signs, physical examinations, and 12-lead ECGs | Approx. 6-12 months | 
| [Phase2] To assess the anti-tumor activity of TRX-221 in patients with the selected EGFR-resistant mutation type | Tumor response rate (ORR) | Approx. 6-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the PK profile of the study treatment | Peak Plasma Concentration (Cmax) | Throughout the study period, an average of 1 year | 
| To evaluate the preliminary anti-tumor activity of the study treatment (Phase 1) | ORR | Approx. 12 months | 
| To evaluate additional anti-tumor activity of the study treatment other than the primary endpoint (Phase 2) | PFS | Approx. 12 months | 
| To assess the safety and tolerability of the study treatment (Phase 2) | Incidence and severity of AEs, TEAEs, SAEs Safety and tolerability as noted by laboratory data, vital signs, physical examinations, and 12-lead ECGs | Approx. 12 months |