Study of HA121-28 in Patients With Non-Small Cell Lung Cancer

This study is a multicenter, open-label, single-arm phase II study to evaluate efficacy and safety of HA121-28 tablets in patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC).


Eligibility Criteria:
Inclusion Criteria:

1. Voluntarily participate in this study and sign the informed consent form;
2. Aged 18 \~ 75 years old (inclusive), male or female;
3. Patients with histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer;
4. RET gene fusion, as demonstrated by "Next-generation" sequencing(NGS) method in central laboratory with College of American Pathologists(CAP) or Clinical Laboratory Improvement Amendments(CLIA) certification;
5. Progressive disease after at least one line of standard therapy (including patients with disease progression during or within 6 months of the end of adjuvant therapy);
6. At least one measurable lesion according to RECIST 1.1 (for lesions previously treated with radiation, the lesion can be included as a measurable lesion only if there is clear disease progression after radiotherapy);
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0-1;
8. Adequate organ function, laboratory tests meeting the following criteria:

   * Neutrophil count (ANC) ≥ 1.5 × 10\^9/L (no G-CSF for WBC-elevating therapy within 2 weeks prior to the laboratory test);
   * Platelet count (PLT) ≥ 75 × 10\^9/L (no platelet transfusion or other drugs to promote platelet production within 2 weeks prior to the laboratory test);
   * Hemoglobin (Hb) ≥ 90 g/L; (not receiving red blood cell transfusion or erythropoiesis-stimulating drugs within 2 weeks prior to the laboratory test);
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) (≤ 5.0 × ULN for patients with liver metastases);
   * Serum total bilirubin (TBIL) ≤ 1.5 × ULN;
   * Serum creatinine ≤ 1.5 × ULN;
   * Albumin ≥ 30 g/L;
9. Male and female patients of childbearing age agree to take effective contraceptive measures during treatment and within 6 months after the completion of treatment.

Exclusion Criteria:

1. Had a documented oncogenic driver gene alteration other than RET in NSCLC, ie, activating EGFR, BRAF, or KRAS mutation, MET exon 14 skipping mutation or high-level amplification, and ALK, ROS1, or NTRK1/2/3 gene fusions;
2. Prior treatment with selective RET inhibitors (including investigational selective RET inhibitors, such as LOXO-292, BLU-667, RXDX-105, etc.);
3. Patients who previously received any anti-tumor therapy (including but not limited to chemotherapy, radiotherapy and targeted therapy, etc.) within 4 weeks before the first use of the study drug; traditional Chinese medicine or Chinese patent medicine with anti-tumor indications within 2 weeks; local palliative radiotherapy for the relief of bone metastasis pain within 2 weeks;
4. Abnormal coagulation function (INR \> 1.5 or APTT \> 1.5 × ULN); patients with bleeding tendency (such as active peptic ulcer) or receiving thrombolytic or anticoagulant therapy;
5. Urine routine showed urine protein ≥ + + and 24 h urine protein \> 1.0 g;
6. Patients who have undergone major surgical procedures within 4 weeks before the first dose or are expected to undergo major surgery during the study;
7. Patients with central nervous system (CNS) metastases who present with progressive neurological symptoms or require an increase in corticosteroid dose to control their CNS disease. If a patient requires treatment with corticosteroids for CNS disease, the dose must be stable for two weeks prior to the first dose;
8. Presence of poorly controlled pericardial, pleural, or peritoneal effusion;
9. Interstitial pneumonia requiring steroid therapy, drug-induced pneumonitis, radiation pneumonitis (except for stable radiation pneumonitis);
10. Significant cardiovascular disease, such as heart failure greater than New York Heart Association (NYHA) Class 2, unstable angina, serious arrhythmia, myocardial infarction or stroke within 6 months prior to the first dose, poorly controlled hypertension (defined as systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 100 mmHg on multiple measurements while on medication);
11. Patients who met any of the following criteria will be excluded:

    * QT interval (QTcF) value ≥ 470 ms for females and ≥ 450 ms for males; or congenital long QT syndrome, taking drugs known to prolong QT interval, family history of long QT syndrome;
    * Resting ECG showed any clinically significant abnormalities in rhythm, conduction, or morphology that required clinical intervention;
    * Cardiac ejection fraction less than 50%;
12. Patients with active hepatitis B virus or hepatitis C virus infection:

    * HBsAg positive with HBV DNA higher than the upper limit of normal range of the study site;
    * HCV antibody positive with HCV RNA higher than upper limit of normal range of the site;
13. Human immunodeficiency virus infected (HIV positive);
14. Inability or severe dysphagia;
15. Patients who have suffered from or are complicated with any other malignant tumor within 5 years (except radically resected skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, local prostate cancer, in situ cervical cancer or other carcinoma in situ);
16. Presence of any severe and/or uncontrolled disease that may affect the drug evaluation in the judgment of the investigator, including but not limited to: life-threatening autoimmune system diseases; drug abuse; severe nervous system diseases (such as epilepsy, dementia, etc.); history of severe mental disorders; severe infection, etc.;
17. Pregnant or lactating women;
18. Other conditions that, in the opinion of the investigator, make participation in the study unsuitable.