Study of TPX-0022 in Patients With Advanced NSCLC, Gastric Cancer or Solid Tumors Harboring Genetic Alterations in MET

Study Overview
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Brief Summary
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A phase 1/2, first-in-human, open-label study of the safety, tolerability, PK, and efficacy of the novel MET/CSF1R/SRC inhibitor TPX-0022 in adult subjects with advanced or metastatic NSCLC, Gastric Cancer, or solid tumors harboring genetic alterations in MET. (SHIELD-I)

Detailed Description
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Dose Escalation: To evaluate the overall safety profile of TPX-0022, single and multiple dose PK profiles and preliminary efficacy in adults subjects with advanced solid tumors harboring genetic alterations in MET. Dose Expansion: To evaluate the preliminary efficacy and overall safety profile of TPX-0022 at the RP2D in defined cohorts of adult subjects in NSCLC, Gastric Cancer and advanced solid tumors harboring genetic alterations in MET.

Official Title
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A Phase 1/2 of Study of the Safety, Tolerability, Pharmacokinetics, and Efficacy of TPX-0022 in Adult Subjects With Locally Advanced or Metastatic NSCLC, Gastric Cancer, or Solid Tumors Harboring Genetic Alterations in MET

Conditions
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Advanced Solid Tumor, Metastatic Solid Tumors, MET Gene Alterations

Intervention / Treatment
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* Drug: elzovantinib (TPX-0022)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 (or age ≥ 20 as required by local regulation). Histological or cytological confirmation of advanced/metastatic MET exon 14 skipping mutation (METΔex14) NSCLC, MET amplified NSCLC, or MET amplified gastric cancers as determined by FISH, qPCR or NGS by local liquid biopsy or tissue, solid tumors with MET fusions or oncogenic MET mutations or MET amplified other than GI/NSCLC. ECOG performance status ≤ 1. Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria). Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the study if they meet protocol specified criteria. Adequate organ function. Life expectancy ≥ 12 weeks. Exclusion Criteria: Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy. Presence or history of any other primary malignancy within the past 3 years other than a history of adequately treated basal or squamous cell carcinoma of the skin, or any adequately treated in situ carcinoma. Major surgery within four weeks of the start of therapy. Additional exclusion criteria for subjects with NSCLC with MET alterations: known oncogene mutations (eg, ALK, ROS1, KRAS, EGFR, etc.) for which there are approved therapies. Additional exclusion criteria for subjects with HCC with MET alterations: liver dysfunction greater than Child-Pugh Class A. Clinically significant cardiovascular disease (either active or within six months before enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2. Any of the following cardiac criteria: Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity). Peripheral neuropathy ≥ Grade 2.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 elzovantinib<br>The dose-escalation part of the study will determine the safety, tolerability, MTD, and RP2D of elzovantinib. The dose-expansion part of the study will determine the safety, tolerability, PK, and preliminary efficacy in specific cohorts. Dose expansion cohorts: Cohort I (NSCLC, METΔex14, treatment Naive) Enrollment Closed; Cohort II (NSCLC with METΔex14, MET therapy pre-treated) Enrollment closed; Cohort III (MET amplified NSCLC, GCN≥10); Cohort IV (MET amplified GI cancer GC/GEJ, CRC/HCC, GCN≥10); Cohort V (NSCLC or GI MET amplified, GCN≥5 and < 10); Cohort VI (Solid tumors with MET fusions, or oncogenic MET mutations or MET amplified other than GI/NSCLC | Drug: elzovantinib (TPX-0022)<br>* Oral elzovantinib (TPX-0022) capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of first cycle dose-limiting toxicities (DLTs) of elzovantinib | Evaluate the safety and tolerability of elzovantinib | Within 28 days of the first elzovantinib dose for each patient | 
| Define the Recommended Phase 2 Dose | Determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of elzovantinib | Approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) | Evaluate the overall safety profile of elzovantinib | Approximately 48 months | 
| Cmax (maximum plasma concentration) of elzovantinib | Evaluate the maximum plasma concentration of elzovantinib | Up to 72 hours post-dose | 
| AUC (area under plasma concentration time curve) of elzovantinib | Evaluate the AUC of elzovantinib | Up to 72 hours post-dose | 
| Cmax (maximum plasma concentration) of TPX-0022 under different food intake conditions | Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (Cmax) of elzovantinib at the RP2D | Up to 72 hours post-dose | 
| AUC (area under plasma concentration time curve) of elzovantinib under different food intake conditions | Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (AUC) of elzovantinib at the RP2D | Up to 72 hours post-dose | 
| Preliminary Objective Response Rate (ORR) | Determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) of elzovantinib | Approximately 48 months | 
| Clinical benefit rate (CBR) | Determine the CBR of elzovantinib | Approximately 48 months | 
| Time to response (TTR) | Determine the TTR of elzovantinib | Approximately 48 months | 
| Duration of Response (DOR) | Determine the DOR of elzovantinib | Approximately 48 months | 
| Progression free survival (PFS) | Determine the PFS of elzovantinib | Approximately 48 months | 
| Intracranial tumor response | Determine the intracranial tumor response in subjects with measurable brain metastases, as determined by BICR | Approximately 48 months | 
| Overall survival (OS) | Determine efficacy and safety of elzovantinib | Approximately 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Small Cell Lung, Non Small Cell Lung Cancer, Non-small cell lung cancer, lung cancer, NSCLC, TPX-0022, EGFR wild-type (wt), advanced non-small cell lung cancer, advanced/metastatic disease, Non-small cell lung carcinoma (NSCLC), treatment of lung cancer after first metastasis, treatment of gastric cancer after first metastasis, treatment of hepatocellular cancer after first metastasis, lung adenocarcinoma, Non small cell lung carcinoma, MET exon 14 deletion, MET exon 14 skipping, MET exon 14 mutation, MET mutation, MET amplification, MET inhibitor, MET dysregulation, MET activation, MET signaling, MET pathway, MET fusion, gastric cancer, hepatocellular cancer, SRC, CSF1R, cancer, first in human