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

NCT04161391 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: CA129-1036TPX-0046-01
• Study Type: interventional
• Target: 41
• Locations: 2 countries
• Sites: 21

Brief 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.

Conditions

Non Small Cell Lung Cancer; Medullary Thyroid Cancer; RET Gene Mutation; Metastatic Solid Tumor; Advanced Solid Tumor

Keywords

Non small cell lung cancer; Non-small cell lung cancer; NSCLC; Medullary Thyroid Cancer; MTC; RET gene mutation; RET gene alteration; Advanced non small cell lung cancer; Advanced/metastatic disease; lung cancer; lung adenocarcinoma; Metastatic solid tumor; Advanced Solid Tumors; RET gene fusion; RET inhibitor; SRC; TPX-0046; Thyroid cancer

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Study Arms (1)

TPX-0046

EXPERIMENTAL

The Phase 1 part of the study will determine the safety, tolerability, PK, MTD, and RP2D of TPX-0046. The food-effect sub-study determines the effect of food on a dose of TPX-0046 at the RP2D dose level. The Phase 2 part of the study will determine the safety, tolerability, PK, and preliminary efficacy in specific cohorts. Phase 2 Cohorts: * Cohort I (NSCLC + RET fusion, RET TKI Therapy Naive) * Cohort II (NSCLC + RET fusion, RET TKI Therapy Pre-treated) * Cohort III (MTC + RET mutation, RET TKI Therapy Naive) * Cohort IV (MTC + RET mutation, RET TKI Therapy Pre-treated) * Cohort V (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Naive) * Cohort VI (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Pre-Treated)

Drug: TPX-0046

Interventions

TPX-0046 DRUG

Oral TPX-0046 capsules

TPX-0046

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 (or age ≥ 20 as required by local regulation).
• 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.
• 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.

You may not qualify if:

• 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 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.
• 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).
• Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.
• Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.
• Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.

Sponsors & Collaborators

• Turning Point Therapeutics, Inc.: lead

Study Sites (21)

Local Institution - 2129

La Jolla, California, 92093, United States

Location

Local Institution - 2128

Orange, California, 92868, United States

Location

Local Institution - 2122

Aurora, Colorado, 80045, United States

Location

SCRI - HealthOne Denver

Denver, Colorado, 80218, United States

Location

Local Institution - 2126

Washington D.C., District of Columbia, 20007, United States

Location

Mayo Clinic - Jacksonville

Jacksonville, Florida, 32224, United States

Location

Local Institution - 2130

Tampa, Florida, 33612-9416, United States

Location

Local Institution - 2127

Atlanta, Georgia, 30322, United States

Location

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Local Institution - 2124

Ann Arbor, Michigan, 48109-5000, United States

Location

Local Institution - 2131

Detroit, Michigan, 48201, United States

Location

Mayo Clinic - Arizona

Rochester, Minnesota, 55905, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Local Institution - 2137

Philadelphia, Pennsylvania, 19111, United States

Location

Local Institution - 2120

Houston, Texas, 77030-3721, United States

Location

Baylor College of Medicine - Baylor Heart Clinic

Houston, Texas, 77030, United States

Location

Local Institution - 2135

Fairfax, Virginia, 22031, United States

Location

Local Institution - 2132

Seattle, Washington, 98195, United States

Location

Local Institution - 6320

Seoul, 120-752, South Korea

Location

Related Links

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

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Medullary; Neoplasm Metastasis; Lung Neoplasms; Adenocarcinoma of Lung; Thyroid Neoplasms

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Nerve Tissue; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Limitations and Caveats

As the study enrollment will close prior to completing Phase 1 dose escalation, the Phase 1 food effect substudy, Phase 1 dose expansion, and Phase 2 activities will not take place.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please Email:

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2019
• First Posted: November 13, 2019
• Study Start: December 6, 2019
• Primary Completion: May 22, 2023
• Study Completion: May 22, 2023
• Last Updated: June 13, 2024
• Results First Posted: June 13, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (20); KR (1)