SHIELD-1: Study of TPX-0022 in Patients With Advanced NSCLC, Gastric Cancer or Solid Tumors Harboring Genetic Alterations in MET

Sponsor

Turning Point Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03993873

Collaborator

(none)

330

Enrollment

Locations

Arm

50.4

Anticipated Duration (Months)

13.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel MET/CSF1R/SRC inhibitor TPX-0022 in adult subjects with advanced NSCLC, Gastric Cancer, or solid tumors harboring genetic alterations in MET. The study will proceed in two parts: a dose-escalation and dose-expansion.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor Metastatic Solid Tumors MET Gene Alterations	Drug: TPX-0022	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

330 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 20, 2019

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 TPX-0022 The dose-escalation part of the study will determine the safety, tolerability, MTD, and RP2D of TPX-0022. 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), Cohort II (NSCLC with METΔex14, 1 or 2 lines prior systemic therapy, no prior MET TKI), Cohort III (NSCLC with METΔex14, MET TKI-pretreated, up to 2 additional lines of prior systemic therapy Cohort IV (MET amplified NSCLC, received 1 or 2 lines of prior systemic therapy, no prior MET TKI) Cohort V (MET amplified Gastric or GEJ Cancer, received 1 line of prior systemic therapy, no prior MET TKI Cohort VI (MET amplified Gastric or GEJ Cancer, received 2 lines prior systemic therapy, no prior MET TKI Exploratory Cohort VII (MET amplified NSCLC or Gastric/GEJ Cancer with gene copy number (GCN ≥ 5 and < 10), received 1 or 2 lines of prior systemic therapy, no prior MET TKI	Drug: TPX-0022 Oral TPX-0022 tablets or capsules

Arm

Intervention/Treatment

Experimental: Phase 1 TPX-0022

The dose-escalation part of the study will determine the safety, tolerability, MTD, and RP2D of TPX-0022. 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), Cohort II (NSCLC with METΔex14, 1 or 2 lines prior systemic therapy, no prior MET TKI), Cohort III (NSCLC with METΔex14, MET TKI-pretreated, up to 2 additional lines of prior systemic therapy Cohort IV (MET amplified NSCLC, received 1 or 2 lines of prior systemic therapy, no prior MET TKI) Cohort V (MET amplified Gastric or GEJ Cancer, received 1 line of prior systemic therapy, no prior MET TKI Cohort VI (MET amplified Gastric or GEJ Cancer, received 2 lines prior systemic therapy, no prior MET TKI Exploratory Cohort VII (MET amplified NSCLC or Gastric/GEJ Cancer with gene copy number (GCN ≥ 5 and < 10), received 1 or 2 lines of prior systemic therapy, no prior MET TKI

Drug: TPX-0022

Oral TPX-0022 tablets or capsules

Outcome Measures

Primary Outcome Measures

Incidence of first cycle dose-limiting toxicities (DLTs) of TPX-0022 [Within 28 days of the first TPX-0022 dose for each patient]
Evaluate the safety and tolerability of TPX-0022
Define the Recommended Phase 2 Dose [Approximately 48 months]
Determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of TPX-0022

Secondary Outcome Measures

Adverse events (AEs) [Approximately 48 months]
Evaluate the overall safety profile of TPX-0022
Cmax (maximum plasma concentration) of TPX-0022 [Up to 72 hours post-dose]
Evaluate the maximum plasma concentration of TPX-0022
AUC (area under plasma concentration time curve) of TPX-0022 [Up to 72 hours post-dose]
Evaluate the AUC of TPX-0022
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 TPX-0022 at the RP2D
AUC (area under plasma concentration time curve) 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 (AUC) of TPX-0022 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 TPX-0022
Clinical benefit rate (CBR) [Approximately 48 months]
Determine the CBR of TPX-0022
Time to response (TTR) [Approximately 48 months]
Determine the TTR of TPX-0022
Duration of Response (DOR) [Approximately 48 months]
Determine the DOR of TPX-0022
Progression free survival (PFS) [Approximately 48 months]
Determine the PFS of TPX-0022
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 TPX-0022

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
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 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 drivers (ALK, ROS1, or EGFR) conferring sensitivity to targeted 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Irvine Chao Family Comprehensive Cancer Center	Irvine	California	United States	92868
2	University California San Diego Moores Cancer Center	San Diego	California	United States	92093
3	Sarah Cannon Research Institute at HealthONE	Denver	Colorado	United States	80218
4	University of Chicago	Chicago	Illinois	United States	60637
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	University of Michigan Rogel Cancer Center	Ann Arbor	Michigan	United States	48109
8	Henry Ford Hospital	Detroit	Michigan	United States	48202
9	Washington University School of Medicine in St. Louis	Saint Louis	Missouri	United States	63110
10	University of Toledo Medical Center	Toledo	Ohio	United States	43614
11	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
12	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
13	Hopital Michallon	La Tronche		France	38700
14	Centre Lyon Berard	Lyon		France	69373
15	Hopital d'Instruction des Armees de Begin - Clinical Research Unit	Saint-Mande		France	94160
16	Institut Gustave Roussy	Villejuif		France	94800
17	Samsung Medical Center	Seoul	Gangnam-gu	Korea, Republic of	06351
18	Seoul National University Hospital	Seoul	Jongno-gu	Korea, Republic of	03080
19	Yonsei Cancer Center, Severance Hospital	Seoul	Seodaemun-gu	Korea, Republic of	03722
20	Asan Medical Center	Seoul	Songpa-gu	Korea, Republic of	05505
21	Clinica Universidad de Navarra - Madrid	Madrid		Spain	28027
22	Fundación Jiménez Díaz - START Madrid	Madrid		Spain	28040
23	HM Centro Integral Oncológico Clara Campal - START Madrid	Madrid		Spain	28050
24	Clinica Universidad de Navarra	Pamplona		Spain	31008