A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients with Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Turning Point Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Dec 2019 → ongoing

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Turning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb company)

External identifiers

EU CT number

2024-512606-25-00

EudraCT number

2016-003616-13

ClinicalTrials.gov

NCT03093116

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Phase 2 Study
• To determine the confirmed Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor an ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Secondary objectives 6

1. 1. To determine the Duration of Response (DOR), time to response (TTR), and clinical benefit rate (CBR) of repotrectinib, as assessed by BICR, in each subject population expansion cohort.
2. 2. To estimate the progression-free survival (PFS) and overall survival (OS) of subjects treated with repotrectinib with advanced solid tumors that harbor an ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
3. 3. To evaluate the safety and tolerability of repotrectinib when administered at the RP2D in subjects with advanced solid tumors that harbor an ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
4. 4. To determine the intracranial objective response rate (IC-ORR) of repotrectinib and Central Nervous System PFS (CNS-PFS) in subjects presenting with measurable brain metastases at baseline, using modified RECIST Version 1.1 assessment.
5. 5. To confirm PK of repotrectinib at the RP2D.
6. 6. To assess treatment-related symptoms and general health status using validated instruments.

Conditions and MedDRA coding

Advanced Solid Tumors

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002635-PIP02-21

Plan to share IPD

Yes

IPD plan description

BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myer Squibb’s data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1 or NTRK1-3 gene fusion. Note: Locally advanced disease is defined as Stage III when subject is not a candidate for surgery, radiation, or multi-modality therapy and metastatic disease is defined as Stage IV per the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual guidelines (Rami-Porta 2017).
2. 2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:- a) a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility. b) a fluorescence in situ hybridization (FISH) test AND prospective confirmation of fusion status by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment will be accepted to determine molecular eligibility.
3. 3. At least 1 measurable target lesion according to RECIST (Version 1.1) prospectively confirmed by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST (Version 1.1) are eligible.
4. 4. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met: 4a) EXP-1: ROS1 TKI-naïve ROS1+ NSCLC (n=110). • No prior exposure to a ROS1 TKI is allowed. • Up to one prior line of chemotherapy OR immunotherapy is allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
5. 4b) EXP-2: 1 Prior ROS1 TKI and 1 Platinum-based Chemotherapy ROS1+ NSCLC (n=120). • Disease progression, or intolerant to one prior line of a ROS1 TKI. • ROS1 TKIs used in a prior line of treatment are limited to crizotinib, ceritinib, entrectinib, or lorlatinib. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would not be eligible for EXP-2). • In addition, the subject must have received one prior line of platinumbased chemotherapy OR one prior line of platinum-based chemotherapy in combination with immunotherapy before or after a ROS1 TKI (Note: subject is not eligible if he/she has been treated with more than one line of chemotherapy OR has received immunotherapy alone).
6. 4c) EXP-3: 2 Prior ROS1 TKIs and NO Chemotherapy or Immunotherapy ROS1+ NSCLC (n=80). • Disease progression, or intolerant to 2 prior lines of a ROS1 TKI treatment. • ROS1 TKIs used in prior lines of treatment are limited to crizotinib, ceritinib, entrectinib, lorlatinib, brigatinib, ensartinib, or cabozantinib. Other prior ROS1 TKI agents that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if 2 different ROS1 TKIs are utilized, or the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would be eligible). • No prior lines of chemotherapy or immunotherapy are allowed.
7. 4d) EXP-4: 1 Prior ROS1 TKI and NO Chemotherapy or Immunotherapy ROS1+ NSCLC (n=120). • Disease progression or intolerant to one prior line of a ROS1 TKI. • ROS1 TKIs used in a prior line of treatment are limited to crizotinib, ceritinib, entrectinib, or lorlatinib. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (eg, if the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would not be eligible for EXP-4). • Note: No prior lines of chemotherapy or immunotherapy are allowed.
8. 4e) EXP-5: TRK TKI-naïve NTRK+ solid tumors (n=approx. 80). • No prior exposure to a TRK TKI is allowed. • Any number of prior lines of chemo or immunotherapy is allowed. • Subjects with NSCLC are not allowed.
9. 4f) EXP-6: TRK TKI-pretreated NTRK+ solid tumors (n=approx. 120). • Disease progression, or intolerant to 1 or 2 prior TRK TKIs. • TRK TKI used in prior lines of treatment are limited to entrectinib, larotrectinib, or selitrectinib (LOXO-195) and cabozantinib. Other prior TRK TKIs that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure of a TRK TKI is considered as one prior line of TKI treatment, (e.g., if 2 different TRK TKIs are utilized or the same TRK TKI was used before and after a chemo- or other systemic therapy, it is counted as 2 prior TKIs and the subject would be eligible). • Any number of prior lines of chemo- or immunotherapy are allowed. • Subjects with NSCLC are not allowed. Please see protocol pages 83-88 for the full inclusion criteria.

Exclusion criteria 13

1. 1. Concurrent participation in another therapeutic clinical trial.
2. 2. Symptomatic brain metastases or leptomeningeal involvement.
3. 3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been completely resected.
4. 4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours prior to study entry.
5. 5. Clinically significant cardiovascular disease (either active or within 6 months prior to 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 grade ≥2.
6. 6. 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 (QTcF) > 470 msec obtained from 3 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, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
7. 7. Known active infections requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity).
8. 8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
9. 9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia grade ≥2.
10. 10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior radiation pneumonitis are not excluded.
11. 11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study, or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
12. 12. Current use or anticipated need for drugs that are known to be strong CYP3A inhibitors or inducers as listed in Appendix 6 of the protocol.
13. 13. Hypersensitivity to the active substance or to any of the excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR) as assessed by BICR using RECIST Version 1.1, in each subject population expansion cohort of solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Secondary endpoints 7

1. 1. Duration of Response (DOR)
2. 2. Time to Response (TTR)
3. 3. Clinical Benefit Rate (CBR)
4. 4. Intracranial Objective Response Rate
5. 5. CNS Progression-Free Survival (CNS-PFS)
6. 6. Progression-Free Survival (PFS)
7. 7. Overall Survival (OS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Turning Point Therapeutics Inc.

Sponsor organisation

Turning Point Therapeutics Inc.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543

Country

United States

Scientific contact point

Organisation

Turning Point Therapeutics Inc.

Contact name

GSM-CT

Public contact point

Organisation

Turning Point Therapeutics Inc.

Contact name

GSM-CT

Third parties 8

Locations

9 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 223 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications