Clinical trial NCT06564324: A Phase III Study Comparing Taletrectinib With Standard Therapy in ROS1 Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients
Official title: A Phase 3 Multicenter Open-label Study of Taletrectinib Versus a Standard of Care ROS1-Tyrosine Kinase Inhibitor (Crizotinib) in TKI-Naïve Patients With ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (TRUST-III)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer
Lead sponsor: Nuvation Bio Inc.
Sponsor class: INDUSTRY
Collaborators: name: AnHeart Therapeutics Inc.
First posted: 2024-08-21
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3, randomized, open-label, comparative, multicenter, international study for NSCLC patients whose tumor tissue exhibits ROS1 fusion positivity (i.e., ROS1+) and who have not previously received an ROS1-targeted TKI (i.e., ROS1-TKI-naïve).

Approximately 138 ROS-1 TKI- naïve ROS1+NSCLC patients will be randomized in a 1:1 ration to one of 2 study arms:

* Arm A: Taletrectinib monotherapy at 600 mg once daily (QD), continuously;
* Arm B: Crizotinib monotherapy at 250 mg twice daily (BID), continuously. Each cycle duration will be 28 days.

Participants will be stratified by the presence of intracranial metastases at baseline (Yes versus No) and prior chemotherapy use for locally advanced or metastatic disease (Yes versus No). For the purposes of stratification, prior chemotherapy is defined as completion of ≥1 cycle of chemotherapy in the locally advanced or metastatic setting. Participants will be treated until they experience progressive disease (PD) assessed by the BIRC, intolerable toxicity, or another discontinuation criterion is met. Crossover from control group (crizotinib) to taletrectinib is also permitted, at the Investigator's discretion with the Sponsor's approval, for qualifying participants who have experienced objective progression confirmed by the BIRC.


Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of locally advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC.
2. Have documentation of ROS1 rearrangement by a positive result
3. Have at least 1 measurable (i.e., target) lesion by Investigator assessment per RECIST v1.1.
4. Prior brain or leptomeningeal metastases allowed if asymptomatic and diagnosed incidentally at study baseline. If participants have neurological symptoms or signs due to CNS metastasis, participants need to complete local therapy (surgery and/or radiation) at least 7 days before enrollment and be clinically stable without requiring for an increasing dose of corticosteroids or use of anticonvulsants to control symptoms.
5. Age ≥18 years (or ≥20 years as required by local regulations).
6. Eastern Cooperative Oncology Group (ECOG) performance status zero (0) to 1.
7. Minimum life expectancy of 3 months or more.
8. Adequate organ function meeting the following criteria:

   1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤3.0 × upper limit of normal (ULN) (or ≤5.0 × ULN, for participants with concurrent liver metastases).
   2. Serum total bilirubin: ≤1.5 × ULN (≤3.0 × ULN for participants with Gilbert syndrome).
   3. Absolute neutrophil count: ≥1500/μL.
   4. Platelet count: ≥75,000/μL.
   5. Hemoglobin: ≥9.0 g/dL.
   6. Estimated creatinine clearance (CLcr) ≥45 mL/min as calculated using the method standard for the institution (e.g., Cockcroft-Gault Equation, i.e., CCr={((140-age)×weight)/(72×SCr)}×0.85 (if female) (Cockcroft and Gault 1976).
9. All toxicities from prior anticancer therapy have resolved to ≤ Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0), or have resolved to previous baseline, at the time of randomization.
10. The participant is willing and capable of giving written informed consent.

Exclusion Criteria:

1. Previously received an investigational antineoplastic agent for NSCLC.
2. Previously received any prior TKI, including ROS1-targeted TKIs.
3. Received immune checkpoint inhibitors for locally advanced or metastatic disease.
4. Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease.
5. Had major surgery within 28 days prior to randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
6. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at Screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization. Participants with no prior history of signs or symptoms of CNS metastases but who receive prophylactic steroids or anticonvulsants are allowed.
7. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.
8. Uncontrolled pleural, abdominal, or pericardial effusion within 28 days prior to randomization, which is associated with malignant effusion requiring recurrent drainage procedures (once monthly or more frequently).
9. Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or participants with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
10. Have clinically significant cardiovascular diseases within 6 months prior to randomization: myocardial infarction, severe/unstable angina, coronary/peripheral endovascular treatment, heart failure, cerebrovascular disorder including transient ischemic attack, pulmonary embolism, deep venous thrombosis and or other clinically significant thrombosis.
11. Have a known history of uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure.
12. Have ongoing cardiac dysrhythmias of ≥CTCAE Grade 2, uncontrolled atrial fibrillation of any grade, or QT interval corrected for heart rate by Fredericia's formula (QTcF) \>470 milliseconds (female) or \>450 milliseconds (male), or symptomatic bradycardia \<45 bpm within 6 months before enrollment; participants treated with medications known to be associated with the development of TdP .
13. Have active and clinically significant bacterial, fungal, or viral infection including but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), known HIV or AIDS-related illness
14. Currently have or have a history of interstitial lung disease (ILD), drug-related pneumonitis, or radiation pneumonitis that required steroid treatment.
15. Be pregnant or breastfeeding

Primary outcomes:
measure: PFS (Assessed by BIRC)
timeFrame: About 49 months
Secondary outcomes:
measure: PFS (Assessed by investigator)
timeFrame: About 69months
measure: ORR
timeFrame: About 69 months
measure: DOR
timeFrame: About 69 months
measure: DCR
timeFrame: About 69 months
measure: TTR
timeFrame: About 69 months
measure: OS
timeFrame: About 69 months
measure: IC-TTP
timeFrame: About 69 months
measure: IC-ORR
timeFrame: About 69 months
measure: IC-DOR
timeFrame: About 69 months
measure: IC-PFS
timeFrame: About 69 months
measure: IC-PR at 6, 12, 18, 24, and 36 months
timeFrame: About 69 months
measure: AE
timeFrame: About 69 months
measure: Taletrectinib concentration in plasma
timeFrame: About 12 months, at the begining of cycle 1, cycle 2, cycle 7 and cycle 12（each cycle is 28 days）
measure: patient-reported outcomes(PRO) assessed by EORTC QLQ-C30
timeFrame: About 69 months
measure: PRO assessed by EORTC QLQ-L13
timeFrame: About 69 months
measure: PRO assessed by EQ-5D-5L
timeFrame: About 69 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University
state: Fujian
city: Nanning
country: China
facility: Guangxi Medical University Cancer Hospital
state: Guangxi
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Jinan
country: China
facility: Cancer Hospital of Shandong First Medical University
state: Shangdong
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
state: Shanghai
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shanxi
Study officials:
affiliation: Shanghai East Hospital
name: Caicun Zhou
role: PRINCIPAL_INVESTIGATOR
References: