Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations

Non Small Cell Lung Cancer Clinical Trial

Official title:

A Phase 1/2 Study of TPX-0046, A Novel Oral RET/SRC Inhibitor in Adult Subjects With Advanced/Metastatic Solid Tumors Harboring Oncogenic RET Fusions or Mutations

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04161391
• Other study ID #: CA129-1036
• Secondary ID: CA129-1036TPX-00
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: December 6, 2019
• Est. completion date: May 22, 2023

Study information

• Verified date: May 2024
• Source: Turning Point Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring RET mutations or alterations. The study consists of three portions: 1) Phase 1 Dose Escalation and Food Effect Sub-study, and 2) Phase 1 dose expansion and 3) Phase 2 efficacy evaluation.

Description:

Phase 1 Dose Escalation and Dose Expansion: To evaluate the overall safety profile, characterize the PK profiles and assess the preliminary efficacy of TPX-0046 in adults subjects with advanced solid tumors harboring oncogenic RET fusions or mutations.

Food Effect Sub-Study: To determine the effect of food on PK of TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring oncogenic RET fusions or mutations.

Phase 2 Efficacy Evaluation: To determine the overall safety and anti-tumor efficacy of TPX-0046 in defined cohorts of subjects with advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 41
• Est. completion date: May 22, 2023
• Est. primary completion date: May 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 (or age = 20 as required by local regulation).

2. Histological or cytological confirmation of advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations, who either have disease progression on, or are intolerant to standard therapy; OR are ineligible for standard therapy or for whom no standard therapy exists; OR are unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the Investigator OR have declined standard therapy.

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 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. 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.

5. 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

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

7. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.

8. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

9. Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Medullary Thyroid Cancer
• Metastatic Solid Tumor
• Neoplasms
• Non Small Cell Lung Cancer
• RET Gene Mutation
• Thyroid Neoplasms

Intervention

Drug:
• TPX-0046
Oral TPX-0046 capsules

Locations

Country	Name	City	State
Korea, Republic of	Local Institution - 6320	Seoul
United States	Local Institution - 2124	Ann Arbor	Michigan
United States	Local Institution - 2127	Atlanta	Georgia
United States	Local Institution - 2122	Aurora	Colorado
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago Medicine	Chicago	Illinois
United States	SCRI - HealthOne Denver	Denver	Colorado
United States	Local Institution - 2131	Detroit	Michigan
United States	Local Institution - 2135	Fairfax	Virginia
United States	Baylor College of Medicine - Baylor Heart Clinic	Houston	Texas
United States	Local Institution - 2120	Houston	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Local Institution - 2129	La Jolla	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Local Institution - 2128	Orange	California
United States	Local Institution - 2137	Philadelphia	Pennsylvania
United States	Mayo Clinic - Arizona	Rochester	Minnesota
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Local Institution - 2132	Seattle	Washington
United States	Local Institution - 2130	Tampa	Florida
United States	Local Institution - 2126	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Turning Point Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046	Participants are eligible for DLT evaluation if they experience a DLT after at least one dose of TPX-0046, or do not experience a DLT after taking at least 75% of the doses expected during the DLT evaluation period. Some adverse events, graded using Common Terminology for Adverse Events (CTCAE) v. 5.0, for defining DLTs include: Toxicities resulting in an excessive number of missed doses; Hematologic: CTCAE grade = 4 neutropenia, CTCAE grade = 4 platelet count decrease, CTCAE grade = 4 anemia, CTCAE grade = 3 febrile neutropenia; Renal: CTCAE grade = 3 creatinine increase; Hepatic: CTCAE grade = 3 total bilirubin elevation; Pancreatic: CTCAE grade 3 serum amylase or lipase increased with clinical symptoms or any grade = serum amylase; Cardiac: CTCAE grade = 3; Other AEs: CTCAE grade 3 vomiting or nausea that does not resolve to grade = 1 within 4 days despite optimal anti-emetic therapy or any grade = 4 vomiting	28 days following the first highest dose of the dose regimen administered in Cycle 1
Primary	Maximum Tolerated Dose (MTD) of TPX-0046	The MTD is defined as the highest dose level of TPX-0046 observed to cause a dose limiting toxicity (DLT) in fewer than 33% of the treated participants in the first treatment cycle (ie, Cycle 1, 28 days).	28 days following the first highest dose of the dose regimen administered in Cycle 1

External Links

•   BMS Clinical Trial Information
•   BMS Clinical Trial Patient Recruiting
•   FDA Safety Alerts and Recalls