A Study of NX-019 in Patients With Advanced, Epidermal Growth Factor Receptor (EGFR) Mutant Cancer

Study Overview
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Brief Summary
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This is a 2-part, first-in-human, open-label study to determine the safety and tolerability of NX-019 and preliminary efficacy in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutant cancer.

Detailed Description
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Part 1: The primary objective of Part 1 of this study is to evaluate the safety and tolerability of NX-019 and to determine the maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D). Part 2: The primary objective of Part 2 of this study is to confirm the safety and tolerability of NX-019 at the MTD/RP2D and, for each expansion cohort, the preliminary evidence of efficacy as measured by objective response rate (ORR).

Official Title
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A First-in-Human, Open-Label, Dose Escalation and Expansion Study of Orally Administered NX-019 in Patients With Advanced, EGFR Mutant Cancer

Conditions
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EGFR Mutation-Related Tumors

Intervention / Treatment
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* Drug: NX-019


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, locally advanced, or metastatic EGFR-mutant cancer and has progressed on or are intolerant to all standard therapy. Patients with non-small cell lung cancer (NSCLC) harboring a mutation that is sensitive to osimertinib must have received osimertinib prior to enrollment. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (evaluable disease acceptable for dose escalation part of study). ≥18 years of age. Life expectancy ≥3 months. Adequate organ and bone marrow function. All patients will have a baseline magnetic resonance imaging (MRI) of the brain. Resolution of any clinically significant toxic effects of prior therapy to Grade 0 or 1 according to the National Cancer Institute CTCAE v5.0 (exception of alopecia and Grade 2 peripheral neuropathy). Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Willingness of men and women of reproductive potential to observe conventional and effective birth control methods with failure rates of <1% for the duration of treatment and for 3 months following the last dose of study treatment. A negative serum pregnancy test at Screening and a negative (serum or urine) pregnancy test within 72 hours before the first dose of study drug (female patients of childbearing potential only). Willing and able to give informed consent and comply with protocol requirements for the duration of the study. Specific Inclusion Criteria for Expansion Cohorts: To be eligible during the expansion part of the study, patients must meet the above inclusion criteria, and the criteria for 1 of the following cohorts: Expansion Cohort 1: Patients with EGFR mutant NSCLC (excluding ex20ins mutations) with CNS lesion(s), including asymptomatic leptomeningeal disease, which have progressed or been detected after prior therapy. Expansion Cohort 2: Patients with EGFR ex20ins-mutant NSCLC with CNS lesion(s), including asymptomatic leptomeningeal disease. Expansion Cohort 3: Patients with NSCLC and EGFR ex20ins mutations, and no prior ex20ins mutation targeted therapy. Expansion Cohort 4: Patients with NSCLC and rare EGFR mutations for which there is no current targeted therapy, excluding exon 19, exon 21 L858R or L861Q, and ex20ins mutations. Expansion Cohort 5: Patients with EGFR mutant NSCLC who meet Inclusion Criterion #1 and do not meet the specific requirements for Expansion Cohorts 1 through 4, after discussion with sponsor. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from participation in the study: Known C797X EGFR mutations or known second driver of disease. Received systemic anticancer chemotherapy, targeted agents, antibody therapy for cancer, immunotherapy for cancer, hormonal therapy or an investigational agent within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study drug treatment. Major surgery within 3 weeks prior to start of study drug treatment. Radiation therapy within 4 weeks prior to start of study drug treatment. Severe or unstable cardiac conditions within 6 months prior to starting study drug treatment. Severe or unstable medical condition including uncontrolled diabetes or unstable psychiatric condition. Dependent on contact lenses (unable to wear eyeglasses) or unable to comply with ophthalmic guidance. History of interstitial lung disease, radiation pneumonitis which required systemic steroid therapy, or other significant lung disease. Has a history of another active malignancy (a second cancer). Active infection requiring systemic therapy. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) (i.e., hepatitis B surface antigen-positive), or hepatitis C virus (HCV) (i.e., detectable HCV ribonucleic acid [RNA]). Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or conditions that may impact drug absorption. Pregnant or breastfeeding. Is using a strong CYP3A inhibitor or inducer. Any other condition, including significant skin or nail disease, that in the opinion of the Investigator would place the patient at an unacceptable risk or cause the patient to be unlikely to fully participate or comply with study procedures.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: NX-019 Dose Escalation<br>Patients will be treated with NX-019 in multiple ascending cohorts. | Drug: NX-019<br>* NX-019 will be administered orally.<br>|
| Experimental: Part 2: NX-019 Dose Expansion<br>Patients will be treated with the MTD/RP2D of NX-019 as determined in Part 1. | Drug: NX-019<br>* NX-019 will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Incidence of Treatment-emergent Adverse Events (TEAEs) |  | Up to 4.5 years | 
| Part 1 and Part 2: Incidence of Adverse Events of Special Interest (AESIs) |  | Up to 4.5 years | 
| Part 1 and Part 2: Incidence of Serious Adverse Events (SAEs) |  | Up to 4.5 years | 
| Part 2: Objective response rate |  | Up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective response rate of NX-019 |  | Up to 4.5 years | 
| Part 1 and Part 2: Plasma Concentration of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Cerebrospinal Fluid (CSF) Concentration of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Maximum Observed Serum Concentration (Cmax) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Area under the concentration versus time curve (AUC) over a dosing interval (AUCtau) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: AUC from time 0 to the time of last quantifiable plasma concentration (AUC0-t) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: AUC from time 0 to infinity (AUC0-inf) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Percent of AUC extrapolated (AUC%extrap) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Terminal phase elimination half-life (t½) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Terminal phase elimination rate constant (λz) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Apparent plasma clearance (CL/F) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Apparent volume of distribution (Vd/F) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Accumulation index using Cmax (AICmax) and accumulation index using AUC (AIAUC0-inf) of NX-019 |  | Up to 43 days | 
| Part 1 and Part 2: Time to Response (TTR) |  | Up to 4.5 years | 
| Part 1 and Part 2: Duration of Response (DOR) |  | Up to 4.5 years | 
| Part 1 and Part 2: Disease Control Rate (DCR) |  | Up to 4.5 years | 
| Part 1 and Part 2: Overall Survival (OS) |  | Up to 4.5 years | 
| Part 1 and Part 2: Objective response rate for CNS (central nervous system) metastases |  | Up to 4.5 years | 
| Part 1 and Part 2: TTR for CNS (central nervous system) metastases |  | Up to 4.5 years | 
| Part 1 and Part 2: DOR for CNS (central nervous system) metastases |  | Up to 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NX-019, EGFR Mutant Cancer, CNS Metastasis