A Phase I/II, 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)
Study Identifier:
TPX-0005-01
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
N/A
Recruiting
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Study Summary
Phase I dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Phase II will determine the confirmed Overall 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 ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS) overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
To study the safety, tolerability, pharmacokinetics, and anti-tumor activity of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements
To report updated results in TKI-naïve and -pretreated patients with advanced, ROS1 fusion-positive (ROS1+) NSCLCs.
Safety and tolerability are also assessed.
ASCO 2023
Endpoints included confirmed objective response rate (cORR) and duration of response (DOR) by blinded independent central review (BICR; RECIST v1.1); intracranial ORR (icORR) in pts with measurable brain mets at BL by BICR per mRECIST v1.1; and safety.
To report efficacy with a minimum follow-up of 14 months (mo) from start of treatment in two ROS1+ NSCLC primary efficacy cohorts and safety in all pts treated at the recommended phase 2 dose (RP2D).
We report updated efficacy with a median follow-up of 33.9 months (mo) [~10 mo of additional follow-up], the first analyses of progression patterns, treatment beyond progression, and an update on subsequent anticancer therapies.
Treatment beyond BICR-assessed progression and sites of progression (per investigator) were also assessed. Safety assessments included all treated pts.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
12 - 64 Years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
Inclusion criteria
- Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests.
- ECOG PS 0-1.
- Age > or = 18 (or age > or = = 20 of age as required by local regulation).
- Capability to swallow capsules intact (without chewing, crushing, or opening).
- At least 1 measurable target lesion according to RECIST version 1.1. CNS-only measurable disease as defined by RECIST version 1.1 is allowed.
- Prior cytotoxic chemotherapy is allowed.
- Prior immunotherapy is allowed.
- Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
- Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
- Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) > or = 1500/mm3 (1.5 × 109/L); Platelets (PLTs) > or = 100,000/mm3 (100 × 109/L); Hemoglobin > or = 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade < or = 1 with or without supplementation
- Life expectancy > or = 3 months
- PHASE 2 Key Inclusion Criteria
- 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.
- Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:
- a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility.
- Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic laboratory for retrospective confirmation by a central diagnostic laboratory test selected by the Sponsor.
- OR
- 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.
- Adequate tumor tissue must be sent to the Sponsor designated central diagnostic laboratory for prospective confirmation by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
- Age > or =12 (or age > or = 20 as required by local regulation).
- Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent or an Assent signed by a parent or legal guardian for subjects age 12 to 17.
- At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to enrollment. Subjects with CNS-only measurable disease > or =10 mm as defined by RECIST (v1.1) are eligible.
- 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.
- EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv. EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
- Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
- Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) > or =1500/mm3 (1.5 × 109/L); Platelets (PLTs) > or =100,000/mm3 (100 × 109/L); Hemoglobin > or = 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade < or = 1 with or without supplementation
- Life expectancy > or = 3 months.
- Subject must have a documented ROS1, ALK or NTRK1-3 gene fusion that has been identified by local testing AND that has been prospectively confirmed by a central diagnostic laboratory selected by the Sponsor to determine molecular eligibility PRIOR to enrollment.
- - Subjects with advanced solid tumors harboring ALK, ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met:
- EXP-1: ROS1 TKI-naïve ROS1+ NSCLC (n=55).
- • 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).
- EXP-2: 1 Prior ROS1 TKI ROS1+ NSCLC (n=100).
- • Disease progression, unresponsive, 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).
- • Up to one prior line of chemotherapy OR immunotherapy before or after a ROS1 TKI is allowed (chemo- or immunotherapy-based ombination regimen is considered as one line of treatment).
- EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (n=40).
- • Disease progression, unresponsive, 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).
- • Up to one prior line of chemotherapy OR immunotherapy pre-TKI or post-TKI is allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
- EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC) (n=12-26).
- • No prior exposure to a ROS1 or ALK TKI is allowed.
- • Up to 2 prior lines of chemo or immunotherapy are allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
- EXP-5: TRK TKI-naïve NTRK+ solid tumors (n=55).
- • No prior exposure to a TRK TKI is allowed.
- • Any number of prior lines of chemo or immunotherapy is allowed.
- EXP-6: TRK TKI-pretreated NTRK+ solid tumors (n=40).
- • Disease progression, unresponsive, or intolerant to 1 or 2 prior TRK TKIs.
- • TRK TKIs used in prior lines of treatment are limited to entrectinib, larotrectinib, or LOXO-195. 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.
Exclusion criteria
- 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.
- Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:
- a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility.
- Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic laboratory for retrospective confirmation by a central diagnostic laboratory test selected by the Sponsor.
- OR
- 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.
- Adequate tumor tissue must be sent to the Sponsor designated central diagnostic laboratory for prospective confirmation by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
- Age > or = 12 (or age > or = 20 as required by local regulation).
- Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent or an Assent signed by a parent or legal guardian for subjects age 12 to 17.
- At least 1 measurable target lesion according to RECIST (v1.1) 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 (v1.1) are eligible.
- 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.
- i. EXP-1: ROS1 TKI-naive ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv. EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naive NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
- Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
- Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) =1500/mm3 (1.5 × 109/L); Platelets (PLTs) > or = 100,000/mm3 (100 × 109/L); Hemoglobin = 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade < or = 1 with or without supplementation
- Life expectancy > or = 3 months.
- Key Exclusion Criteria PHASE 1 and PHASE 2
- Concurrent participation in another therapeutic clinical trial.
- Symptomatic brain metastases or leptomeningeal involvement.
- 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, requiring therapy within the previous 2 years.
- 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 (< or = 10 fractions) must have been completed at least 48 hours prior to study entry
- 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 > or = II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade > or = 2
- 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.
- Known active infections (bacterial, fungal, viral including HIV positivity).
- Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.
- Peripheral neuropathy of CTCAE > or = grade 2.
- 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.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (FJD)
Madrid, Spain, 28040
Investigator
Victor Moreno Garcia
Status
Recruiting
Condition(s) Treated at Site
Solid Tumor
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Recruiting
Condition(s) Treated at Site
Solid Tumor