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

Phase 1

Active, not recruiting

• Conditions: Advanced Solid Tumor; MET Gene Alterations; Metastatic Solid Tumors
• Interventions: Drug: elzovantinib (TPX-0022)

• Registration Number: NCT03993873
• Lead Sponsor: Turning Point Therapeutics, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-06-13
• Study First Submitted QC: 2019-06-19
• Study First Posted: 2019-06-21
• Study Start: 2019-09-05
• Primary Completion: 2024-01-08
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-18
• Last Update Posted: 2024-12-20
• Study Completion: 2026-03-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 95

Inclusion Criteria

1. Age ≥ 18 (or age ≥ 20 as required by local regulation).
2. 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.
3. ECOG performance status ≤ 1.
4. Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria).
5. Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the study if they meet protocol specified criteria.
6. Adequate organ function.
7. Life expectancy ≥ 12 weeks.

Exclusion Criteria

1. Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.

2. 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.

3. Major surgery within four weeks of the start of therapy.

4. 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.

5. Additional exclusion criteria for subjects with HCC with MET alterations: liver dysfunction greater than Child-Pugh Class A.

6. 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.

7. 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

8. Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).

9. Peripheral neuropathy ≥ Grade 2.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1 elzovantinib	elzovantinib (TPX-0022)	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (24)

Local Institution - 2102; 🇺🇸 La Jolla, California, United States

Local Institution - 2108; 🇺🇸 Orange, California, United States

Local Institution - 2105; 🇺🇸 Denver, Colorado, United States

Local Institution - 2111; 🇺🇸 Chicago, Illinois, United States

Local Institution - 2107; 🇺🇸 Boston, Massachusetts, United States

Local Institution - 2109; 🇺🇸 Boston, Massachusetts, United States

Local Institution - 2106; 🇺🇸 Ann Arbor, Michigan, United States

Local Institution - 2113; 🇺🇸 Detroit, Michigan, United States

Local Institution - 2103; 🇺🇸 Saint Louis, Missouri, United States

Local Institution - 2104; 🇺🇸 Toledo, Ohio, United States

Local Institution - 2101; 🇺🇸 Houston, Texas, United States

Local Institution - 2112; 🇺🇸 Fairfax, Virginia, United States

Local Institution - 4202; 🇫🇷 La Tronche, Rhone-Alpes, France

Local Institution - 4203; 🇫🇷 Saint-Mandé, Val-de-Marne, France

Local Institution - 4204; 🇫🇷 Villejuif, Val-de-Marne, France

Local Institution - 4201; 🇫🇷 Lyon, France

Local Institution - 6304; Seoul, Korea, Democratic People's Republic of

Local Institution - 6301; 🇰🇷 Seoul, Seoul-teukbyeolsi [Seoul], Korea, Republic of

Local Institution - 6303; 🇰🇷 Seoul, Korea, Republic of

Local Institution - 6302; 🇰🇷 Seoul, Korea, Republic of

Local Institution - 4104; 🇪🇸 Madrid, Spain

Local Institution - 4103; 🇪🇸 Madrid, Spain

Local Institution - 4101; 🇪🇸 Madrid, Spain

Local Institution - 4102; 🇪🇸 Pamplona, Spain