REPOTRECTINIB for Advanced solid tumors

Inclusion criteria

• {"criterion_text":"- 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).\n- 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.\n- 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.\n- 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).\n- 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 platinum-based 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).\n- 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.\n- 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.\n- 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.\n- 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

• {"criterion_text":"- 1. Concurrent participation in another therapeutic clinical trial.\n- 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.\n- 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.\n- 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.\n- 13. Hypersensitivity to the active substance or to any of the excipients.\n- 2. Symptomatic brain metastases or leptomeningeal involvement.\n- 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.\n- 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.\n- 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.\n- 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\n- 7. Known active infections requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity).\n- 8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.\n- 9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia grade ≥2."}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"ORR assessed by Blinded Independent Central Review (BICR) using RECIST Version 1.1."}

Secondary endpoints

• {"endpoint_text":"- 1. Duration of Response (DOR)","definition_or_measurement_approach":"DOR as assessed by Blinded Independent Central Review (BICR) per RECIST v1.1."}
• {"endpoint_text":"- 2. Time to Response (TTR)","definition_or_measurement_approach":"TTR as assessed by BICR per RECIST v1.1."}
• {"endpoint_text":"- 3. Clinical Benefit Rate (CBR)","definition_or_measurement_approach":"CBR as assessed by BICR per RECIST v1.1."}
• {"endpoint_text":"- 4. Intracranial Objective Response Rate","definition_or_measurement_approach":"Intracranial ORR using modified RECIST Version 1.1 assessment for measurable brain metastases."}
• {"endpoint_text":"- 5. CNS Progression-Free Survival (CNS-PFS)","definition_or_measurement_approach":"Time to progression within the central nervous system (CNS-PFS), assessment method per protocol (imaging and RECIST-based CNS criteria)."}
• {"endpoint_text":"- 6. Progression-Free Survival (PFS)","definition_or_measurement_approach":"PFS assessed per RECIST v1.1 and protocol-specified review schedule."}
• {"endpoint_text":"- 7. Overall Survival (OS)","definition_or_measurement_approach":"OS measured from treatment start to death from any cause."}

Other endpoints

• {"endpoint_text":"- 5. To confirm PK of repotrectinib at the RP2D.\n- 6. To assess treatment-related symptoms and general health status using validated instruments.","definition_or_measurement_approach":"PK endpoints: pharmacokinetic sampling and PK parameter estimation at RP2D. Patient-reported outcomes/health status: measured using validated instruments/questionnaires as specified in protocol."}

Methods

• Online advertising via social media (Facebook Ads) targeted to potential participants/patient audiences (materials present: Facebook Ads graphics and text).
• Online advertising via search ads (Google Ads) and website recruitment content (Google Ads graphics and text; Website Content and Website Design documents).
• Dedicated study website and website privacy / cookies policy for recruitment and pre-screening (Website Privacy Policy / Cookies Policy documents).
• Investigator referral (Investigator Referral Letter) distributed to physicians and clinical sites.
• Printed materials: patient brochures and patient flyers for site distribution.
• Pre-screening questionnaires (online or paper) to identify potentially eligible participants.
• Country- and language-specific recruitment materials and PIS/ICF (multiple language versions and country-specific K2 recruitment packages).

Denmark

Latest Decision Or Authorization Date

24-07-2024

Number Of Sites

1

Number Of Participants

3

Hungary

Latest Decision Or Authorization Date

19-07-2024

Number Of Sites

2

Number Of Participants

1

Netherlands

Latest Decision Or Authorization Date

19-07-2024

Number Of Sites

2

Number Of Participants

23

Italy

Latest Decision Or Authorization Date

05-08-2024

Number Of Sites

3

Number Of Participants

20

Germany

Latest Decision Or Authorization Date

24-07-2024

Number Of Sites

2

Number Of Participants

27

France

Latest Decision Or Authorization Date

26-07-2024

Number Of Sites

4

Number Of Participants

38

Spain

Latest Decision Or Authorization Date

22-07-2024

Number Of Sites

4

Number Of Participants

39

Belgium

Latest Decision Or Authorization Date

23-07-2024

Number Of Sites

1

Number Of Participants

9

Poland

Latest Decision Or Authorization Date

04-08-2024

Number Of Sites

2

Number Of Participants

30

Primary sponsor

Full Name

Turning Point Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Perceptive Informatics Inc.

Responsibilities

Medical image analysis/ review - X-ray, MRI, ultrasound, etc.

Name

Premier Research

Responsibilities

Regulatory activities, investigator recruitment, IVRS randomization, E-data capture, SUSAR reporting, QA auditing

Name

CellCarta

Responsibilities

Tumor genetic testing

Name

Bioagilytix Labs LLC

Responsibilities

PK sample collection

Name

PPD Global Central Labs

Responsibilities

Sample management and central laboratory services

Name

Almac Clinical Services LLC

Responsibilities

Biopsy tissue analysis

Name

Pharmaceutical Product Development LLC

Responsibilities

Clinical chemistry and clinical haematology testing

Name

Clario

Responsibilities

ECG data management

Third parties

• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Medical image analysis/ review - X-ray, MRI, ultrasound, etc.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Premier Research","duties_or_roles":"Regulatory (preparation of applications to CA and ethics committee), Investigator recruitment, IVRS – treatment randomization, E-data capture, SUSAR reporting, Quality assurance auditing; (other duties with codes 1,10,11,6)","organisation_type":"Industry"}
• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"Tumor genetic testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"PK Sample collection","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Sample management; laboratory services (codes indicate sample management and other lab duties)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Almac Clinical Services LLC","duties_or_roles":"Biopsy Tissue analysis; other related laboratory services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Clinical chemistry, Clinical haematology","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"ECG data management","organisation_type":"Health care"}