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

• ClinicalTrials.gov Identifier: NCT04161391
• Recruitment Status: Active, not recruiting
• First Posted: November 13, 2019
• Last Update Posted: February 13, 2023
• Sponsor: Turning Point Therapeutics, Inc.
• Information provided by (Responsible Party): Turning Point Therapeutics, Inc.

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 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.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; Medullary Thyroid Cancer; RET Gene Mutation; Metastatic Solid Tumor; Advanced Solid Tumor	Drug: TPX-0046	Phase 1; Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 16, 2019
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: November 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: TPX-0046; 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; Oral TPX-0046 capsules

Outcome Measures

Primary Outcome Measures :

1. Incidence of first cycle dose-limiting toxicities (DLTs) of TPX-0046 [ Time Frame: Within 28 days of the first TPX-0046 dose for each patient ]
   Evaluate the safety and tolerability of TPX-0046
2. Define the Recommended Phase 2 Dose [ Time Frame: Approximately 24 months ]
   Determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of TPX-0046

Secondary Outcome Measures :

1. Adverse events (AEs) [ Time Frame: Approximately 48 months ]
   Evaluate the overall safety profile of TPX-0046

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

UCI Health - Chao Family Comprehensive Cancer Center

Irvine, California, United States, 92868

UC San Diego Moores Cancer Center

San Diego, California, United States, 92093

United States, Colorado

University of Colorado, Denver

Aurora, Colorado, United States, 80045

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, United States, 80218

United States, District of Columbia

Georgetown University Medical Center

Washington, District of Columbia, United States, 20007

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Winship Cancer Institute, Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

University of Chicago Medical Center

Chicago, Illinois, United States, 60637

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10021

United States, Pennsylvania

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Virginia

Virginia Cancer Specialists

Fairfax, Virginia, United States, 22031

United States, Washington

The University of Washington, Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Korea, Republic of

Severance Hospital, Yonsei University Health System

Seoul, Korea, Republic of, 03722

Sponsors and Collaborators

Turning Point Therapeutics, Inc.

Investigators

• Study Director: Turning Point Therapeutics, MD; Turning Point Therapeutics

More Information

• Responsible Party: Turning Point Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04161391
• Other Study ID Numbers: TPX-0046-01
• First Posted: November 13, 2019
• Last Update Posted: February 13, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Turning Point Therapeutics, Inc.:

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

Additional relevant MeSH terms:

Neoplasms; Lung Neoplasms; Thyroid Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Bronchial Neoplasms; Thyroid Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Carcinoma, Non-Small-Cell Lung; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Endocrine System Diseases