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

Phase 1

Terminated

• Conditions: Advanced Solid Tumor; Non Small Cell Lung Cancer; Metastatic Solid Tumor; Medullary Thyroid Cancer; RET Gene Mutation
• Interventions: Drug: TPX-0046

• Registration Number: NCT04161391
• Lead Sponsor: Turning Point Therapeutics, Inc.

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.

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 Timeline

• Study First Submitted: 2019-11-11
• Study First Submitted QC: 2019-11-11
• Study First Posted: 2019-11-13
• Study Start: 2019-12-06
• Primary Completion: 2023-05-22
• Study Completion: 2023-05-22
• Status Verified: 2024-05
• Results First Submitted: 2024-05-21
• Results First Submitted QC: 2024-05-21
• Last Update Submitted: 2024-05-21
• Results First Posted: 2024-06-13
• Last Update Posted: 2024-06-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 41

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TPX-0046	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)

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of TPX-0046	28 days following the first highest dose of the dose regimen administered in Cycle 1	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).
Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046	28 days following the first highest dose of the dose regimen administered in Cycle 1	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

Trial Locations

Locations (21)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Local Institution - 2120; 🇺🇸 Houston, Texas, United States

Baylor College of Medicine - Baylor Heart Clinic; 🇺🇸 Houston, Texas, United States

Local Institution - 2132; 🇺🇸 Seattle, Washington, United States

Local Institution - 2122; 🇺🇸 Aurora, Colorado, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

Local Institution - 2128; 🇺🇸 Orange, California, United States

Local Institution - 2129; 🇺🇸 La Jolla, California, United States

Mayo Clinic - Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Local Institution - 2126; 🇺🇸 Washington, District of Columbia, United States

SCRI - HealthOne Denver; 🇺🇸 Denver, Colorado, United States

Local Institution - 2131; 🇺🇸 Detroit, Michigan, United States

Local Institution - 2127; 🇺🇸 Atlanta, Georgia, United States

Local Institution - 2130; 🇺🇸 Tampa, Florida, United States

University of Chicago Medicine; 🇺🇸 Chicago, Illinois, United States

Mayo Clinic - Arizona; 🇺🇸 Rochester, Minnesota, United States

Local Institution - 2124; 🇺🇸 Ann Arbor, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Local Institution - 2137; 🇺🇸 Philadelphia, Pennsylvania, United States

Local Institution - 2135; 🇺🇸 Fairfax, Virginia, United States

Local Institution - 6320; 🇰🇷 Seoul, Korea, Republic of