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

• Sponsor: Turning Point Therapeutics, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04161391
• Collaborator: (none)
• Enrollment: 462
• Locations: 16
• Arm: 1
• Anticipated Duration (Months): 82.5
• Patients Per Site: 28.9
• Patients Per Site Per Month: 0.3

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 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
• Anticipated Enrollment: 462 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: Dec 16, 2019
• Anticipated Primary Completion Date: Dec 1, 2025
• Anticipated Study Completion Date: Nov 1, 2026

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 [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 [Approximately 24 months]

   Determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of TPX-0046

3. Define the objective response rate (ORR) [Approximately 48 months]

   Determine the preliminary efficacy by the ORR in defined cohorts of subjects with advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations.

Secondary Outcome Measures

1. Adverse events (AEs) [Approximately 48 months]

   Evaluate the overall safety profile of TPX-0046

2. Cmax (maximum plasma concentration) of TPX-0046 [Up to 96 hours post-dose]

   Evaluate the maximum plasma concentration of TPX-0046

3. AUC (area under plasma concentration time curve) of TPX-0046 [Up to 96 hours post-dose]

   Determine the AUC of TPX-0046

4. Cmax (maximum plasma concentration) of TPX-0046 under different food intake conditions [Up to 96 hours post-dose]

   Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (Cmax) of TPX-0046 at the RP2D

5. AUC (area under plasma concentration time curve) of TPX-0046 under different food intake conditions [Up to 96 hours post-dose]

   Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (AUC) of TPX-0046 at the RP2D

6. Preliminary Objective Response Rate (ORR) [Approximately 48 months]

   Determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) of TPX-0046

7. Clinical benefit rate (CBR) [Approximately 48 months]

   Determine the CBR of TPX-0046

8. Time to response (TTR) [Approximately 48 months]

   Determine the TTR of TPX-0046

9. Duration of Response (DOR) [Approximately 48 months]

   Determine the DOR of TPX-0046

10. Progression free survival (PFS) [Approximately 48 months]

    Determine the PFS of TPX-0046

11. Intracranial tumor response [Approximately 48 months]

    Determine the intracranial tumor response in subjects with measurable brain metastases, as determined by BICR

12. Overall survival (OS) [Approximately 48 months]

    Determine efficacy and safety of TPX-0046

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCI Health - Chao Family Comprehensive Cancer Center	Irvine	California	United States	92868
2	UC San Diego Moores Cancer Center	San Diego	California	United States	92093
3	University of Colorado, Denver	Aurora	Colorado	United States	80045
4	Sarah Cannon Research Institute at HealthONE	Denver	Colorado	United States	80218
5	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
6	Moffitt Cancer Center	Tampa	Florida	United States	33612
7	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322
8	University of Chicago Medical Center	Chicago	Illinois	United States	60637
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
11	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
12	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
13	MD Anderson Cancer Center	Houston	Texas	United States	77030
14	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
15	The University of Washington, Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
16	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Turning Point Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04161391
• Other Study ID Numbers: TPX-0046-01
• First Posted: Nov 13, 2019
• Last Update Posted: Mar 14, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• 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; 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
• Additional relevant MeSH terms: Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms

Study Results

No Results Posted as of Mar 14, 2022