A Phase III Study to Evaluate the Efficacy and Safety of JYP0322 in Previously Untreated ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Laborértékek

• History of severe cardiovascular or cerebrovascular disease, including but not limited to: clinically significant cardiac rhythm or conduction abnormality (e.g., ventricular arrhythmia requiring intervention, 2nd-3rd degree AV block); acute coronary syndrome, congestive heart failure, aortic dissection, severe stable/unstable angina, coronary/peripheral vascular intervention, stroke or other ≥Grade 3 cerebrovascular event (including TIA), pulmonary embolism, DVT or other clinically significant thrombosis within 6 months before randomization; NYHA > Class II heart failure or LVEF < 50%; any uncontrolled atrial fibrillation; QTcF > 470 ms or symptomatic bradycardia < 45 bpm; known congenital long QT syndrome or history of QT prolongation.
  • Active infection requiring IV antibiotics or hospitalization at randomization. Acute flare of dysphagia or GI disease affecting absorption (Crohn's, UC, short bowel syndrome, or other malabsorption).
  • Failure to recover from prior antitumor therapy toxicity to baseline or ≤Grade 1 (CTCAE v5.0), except alopecia, Grade 2 peripheral neuropathy, or hypothyroidism controlled by replacement judged safe by investigator.
  • Major surgical procedure (other than dx/biopsy/drainage) within 4 weeks before randomization, or anticipated major surgery during study; vascular access placement and minor procedures (catheter, core needle biopsy) allowed.
  • Other primary malignancy except: adequately treated melanoma/skin carcinoma/cervical carcinoma in situ; treated non-metastatic prostate cancer; or other primary malignancy with no relapse ≥3 years.
  • Untreated spinal cord compression by tumor. Participated in another interventional trial within 4 weeks before first dose (screen failures exempt).
  • Interstitial fibrosis, ILD, or drug-induced pneumonitis within 6 months before first dose not recovered to Grade 1 (asymptomatic radiation pneumonitis exempt).
  • Systemic anticancer therapy (chemo-based or other) within 14 days or 5 half-lives (whichever shorter, minimum 14 days) before randomization.
  • Clinically uncontrolled serous effusion needing drainage > once/month (pericardial/pleural/ascites), or < 2 weeks observation after last drainage before randomization.
  • History of severe allergy or hypersensitivity to JYP0322 or crizotinib excipients.
  • Active HBV (HBsAg+ and HBV DNA ≥1000 IU/mL or 5000 copies/mL), active HCV (RNA+), syphilis requiring treatment (RPR ≤1:2 with TPHA+ allowed), or HIV infection.
  • Pregnant or lactating. Use of strong CYP3A4 inhibitors/inducers or narrow-therapeutic-index CYP3A4 substrates within 14 days or 5 half-lives (shorter) before randomization, or inability to discontinue during study.
  • Active or recurrent autoimmune disease, depression/affective disorder or suicidal risk, prior bone marrow/organ transplant, or any condition investigator judges unsafe.
  • Uncontrolled hyperthyroidism or hypothyroidism with prior severe comorbidity. Moderate-to-severe hepatic impairment history: prior ≥Grade 3 hepatotoxicity, or serious liver baseline (cirrhosis etc.).
  • Tumor invasion of great vessels (aorta, pulmonary artery/vein, vena cava) on imaging; OR any prior TKI therapy including ROS1-TKI.

• Voluntary participation and signed written informed consent (ICF) before any study-specific procedure.
  • Age ≥ 18 years at screening. Histologically or cytologically confirmed, unresectable locally advanced (AJCC 9th edition stage IIIB or IIIC not amenable to multimodality therapy) or metastatic (stage IV) ROS1-positive non-small cell lung cancer (NSCLC).
  • ROS1 gene rearrangement/fusion positivity confirmed by a qualified local laboratory using PCR, NGS, or FISH. IHC alone is not acceptable. A written report of the ROS1 test must be provided.
  • Sufficient and adequate archival tumor tissue must be available for central laboratory ROS1 retesting per the Central Lab Manual; if no archival tissue is available, a fresh tumor biopsy is required.
  • No prior ROS1 TKI therapy. Prior systemic therapy limited to ≤1 line of standard chemotherapy:
  • A prior chemotherapy-based regimen administered for ≥1 cycle counts as one line.
  • Disease recurrence within 6 months after completion of adjuvant chemotherapy counts that adjuvant regimen as one prior line.
  • Asymptomatic central nervous system (CNS) metastases allowed (leptomeningeal carcinomatosis excluded). Previously treated and controlled/stabilized CNS metastases permitted if:
  • On non-enzyme-inducing antiepileptic drugs (non-EIAED) for seizure prophylaxis; or EIAED discontinued ≥14 days before randomization.
  • If corticosteroids needed, stable or tapering dose ≤10 mg/day prednisone (or equivalent) for ≥14 days before randomization.
  • Prior local therapy (WBRT, SRS/SRT) completed ≥14 days before randomization; treatment-related toxicities (except alopecia) resolved to ≤ Grade 1 (CTCAE v5.0).
  • At least one measurable lesion per RECIST v1.1. ECOG performance status 0-1. Expected survival ≥ 3 months.
  • Adequate organ function within 14 days before randomization (no blood products, growth factors, or platelet/ WBC boosters within 14 days):
• ANC ≥ 1.5 × 10\^9/L
• Platelets ≥ 100 × 10\^9/L
• Hemoglobin ≥ 90 g/L (stable erythropoietin ≥3 months allowed)
• CrCl > 45 mL/min (Cockcroft-Gault)
• Total bilirubin < 1.5 × ULN (Gilbert syndrome ≤ 3.0 × ULN)
• AST and ALT < 2.5 × ULN (< 5 × ULN if liver metastasis)
• APTT and INR < 1.5 × ULN Women of childbearing potential: negative serum pregnancy test within 7 days before randomization. All participants with reproductive potential (male and female) must agree to use highly effective contraception (hormonal, barrier, or abstinence) during treatment and for 6 months after last dose. Willing and able to comply with scheduled visits, treatment, labs, and procedures.