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Clinical Trial 20149

Cancer Type: Thoracic
Study Type: Treatment
NCT#: NCT03093116

Phase: Phase I/II
Principal Investigator: Creelan, Benjamin

Call 813-745-6100
or 1-800-679-0775 Learn More

Overview

Study Title

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)

Summary

This study is to evaluate the anti-cancer activity of repotrectinib

Objective

Primary Objectives for Phase 1 Dose Escalation: To determine the first cycle dose-limiting toxicities (DLTs) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To determine the maximum tolerated dose (MTD) of repotrectinib in adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To determine the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib for adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Primary Objective for 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 ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Secondary Objectives for Phase 1 Dose Escalation: To evaluate the safety and tolerability of repotrectinib at various doses in subjects with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To evaluate the single- and multiple-dose pharmacokinetic (PK) profiles of repotrectinib. To determine the effect of food on the pharmacokinetics (PK) of repotrectinib. To determine the preliminary objective response rate (ORR) by BICR and the clinical benefit rate (CBR) of repotrectinib, in subjects with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To evaluate the potential of repotrectinib to induce cytochrome P450 3A (CYP3A) using midazolam as a probe substrate. Secondary Objectives for Phase 2 Study: 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 of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To estimate the progression-free survival (PFS) and overall survival (OS) of subjects treated with repotrectinib with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. To evaluate the safety and tolerability of repotrectinib when administered at the RP2D in subjects with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. 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 v1.1 assessment. To confirm PK of repotrectinib at the RP2D. To assess treatment-related symptoms and general health status using validated instruments of subject-reported outcomes (EORTC-QLQ-C30 and LC-13 when applicable) in subjects treated with repotrectinib. Exploratory Objectives: To evaluate the pharmacodynamic (PD) effects of repotrectinib in subjects with advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene fusion. To explore the potential prognostic utility of genomic alterations and characterize intrinsic or acquired resistance to repotrectinib using liquid biopsy and tissue samples. To explore association between ORR by subgroups including demographic and baseline risk factors in each expansion cohort (Phase 2 only).

Treatments

Therapies

Therapy (NOS)

Medications

Repotrectinib (); TPX-0005 (Repotrectinib)

Inclusion Criteria

Phase 1

Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests

ECOG PS 0-1

Age >18 (or age > 20 of age as required by local regulation)

Capability to swallow capsules intact

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

Participants with asymptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria

Baseline laboratory values fulfilling requirements per protocol

Life expectancy > 3 months.

PHASE 2

Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor that harbors a ROS1, ALK 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 American Joint Committee on Cancer Eighth Edition Cancer Staging Manual guidelines.

Participants 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

Age >12 (or age > 20 as required by local regulation)

At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed by Blinded Independent Central Radiology Review, selected by Sponsor, PRIOR to enrollment. Participants with CNS-only measurable disease >10 mm as defined by RECIST (v1.1) are eligible

Participants 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

Baseline laboratory values fulfilling requirements per protocol

Life expectancy > 3 months

Exclusion Criteria

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 (≤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 > II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade >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 >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. Participants with history of prior radiation pneumonitis are not excluded

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