Rucaparib Monoclonal Antibody for Lorlatinib-Induced Hypercholesterolemia / Mixed

A Prospective Single-Arm Clinical Study of Recakimab for Lorlatinib-Induced Hypercholesterolemia / Mixed Hyperlipidemia

This prospective single-arm clinical study plans to enroll 29 participants with unresectable stage IIIB-IV ALK fusion-positive non-small cell lung cancer (NSCLC). Eligible patients must be aged ≥18 years with an ECOG performance status of 0-2 and have developed grade 1-3 hypercholesterolemia adverse events (AEs, per CTCAE 5.0) after lorlatinib treatment. All subjects will receive recakimab 300 mg administered once every 8 weeks.

The primary endpoint is the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at week 16. Secondary endpoints include absolute change in LDL-C at week 16; percentage and absolute change in LDL-C at week 32; percentage and absolute changes from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a) [Lp(a)] and triglycerides (TG) at weeks 16 and 32; proportion of patients whose hypercholesterolemia AEs return to normal at weeks 16 and 32; LDL-C target achievement rate at weeks 16 and 32; and safety profile related to recakimab.

Inclusion Criteria:

1. Aged ≥ 18 years on the day of signing the informed consent form, with no gender restriction;
2. Patients with unresectable stage IIIB/IIIC/IV non-small cell lung cancer (NSCLC) confirmed by cytology or histology (staging defined per the 9th edition of the International Association for the Study of Lung Cancer (IASLC) Staging Manual in Thoracic Oncology);
3. Positive ALK fusion confirmed by genetic testing;
4. Developed Grade 1-3 hypercholesterolemia adverse events after lorlatinib treatment (per CTCAE Version 5.0);
5. Fasting triglyceride level ≤ 5.6 mmol/L at screening;
6. Willing and able to comply with scheduled study visits, treatment regimens, laboratory tests and all other study procedures.

Exclusion Criteria:

1. Subjects with known hypersensitivity to the investigational product, or a history of severe hypersensitivity reactions to other antibody-based drugs;

2. Diagnosed with familial hypercholesterolemia per the Simon Broome Criteria;

3. Received other PCSK9 inhibitors within 6 months prior to screening;

4. Uncontrolled hypercholesterolemia (total cholesterol above the upper limit of normal) existed before lorlatinib initiation;

5. Prior diagnosis of New York Heart Association (NYHA) Class III-IV cardiac dysfunction;

6. Prior diagnosis of atherosclerotic cardiovascular disease (ASCVD), including acute coronary syndrome, stable coronary artery disease, post-revascularization status, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack, peripheral atherosclerotic artery disease, etc.;

7. Prior diagnosis of severe arrhythmia, such as recurrent and symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response;

8. Uncontrolled hypertension at screening or randomization (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);

9. Prior diagnosis of diseases that significantly affect lipid levels, including nephrotic syndrome, severe liver disease, Cushing's syndrome, etc.;

10. Prior diagnosis of Type 1 diabetes mellitus, or uncontrolled Type 2 diabetes mellitus at screening (HbA1c >8.5%);

11. Active infectious disease at screening judged by the investigator to render the subject ineligible for trial participation;

12. Participation in another interventional clinical trial within 1 month before screening (excluding screen failures), or within 5 half-lives of the investigational product at screening (whichever duration is longer);

13. History of drug abuse, illicit substance use, or chronic alcohol abuse prior to screening;

14. Major surgery within 3 months before screening, or planned major surgery during the study period;

15. Chronic continuous or repeated systemic glucocorticoid use within 3 months prior to screening (topical administration excluded, e.g., intra-articular, intranasal, inhaled, cutaneous external use; chronic continuous use defined as ≥7 consecutive days; repeated use defined as cumulative administration ≥3 courses);

16. Weight-loss medication use or weight-altering bariatric surgery within 2 months prior to screening;

17. Any laboratory test value meeting the following criteria at screening or randomization:

    1. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² (calculated via the MDRD formula);
    2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN); for patients with liver metastases, ALT/AST >5×ULN; or total bilirubin >1.5×ULN;
    3. Creatine kinase (CK) >3×ULN;
    4. Thyroid-stimulating hormone (TSH) below the lower limit of normal (LLN) or >1.5×ULN;
    5. Positive human immunodeficiency virus antibody (HIV-Ab) or hepatitis C virus antibody (HCV-Ab); positive hepatitis B surface antigen (HBsAg) with HBV-DNA ≥1000 copies/mL (or ≥200 IU/mL; if the assay lower limit exceeds 1000 copies/mL or 200 IU/mL, HBV-DNA ≥ assay lower limit);
    6. Positive pregnancy test;

18. Planned implantation of cardiac pacemaker, cardiac resynchronization therapy (CRT), implantable cardioverter-defibrillator (ICD), or equivalent device during the study period;

19. Positive human immunodeficiency virus antibody (HIV-Ab) or hepatitis C virus antibody (HCV-Ab); positive hepatitis B surface antigen (HBsAg) with HBV-DNA ≥1000 copies/mL (or ≥200 IU/mL; if the assay lower limit exceeds 1000 copies/mL or 200 IU/mL, HBV-DNA ≥ assay lower limit);

20. Judged by the investigator to be unsuitable for subcutaneous injection;

21. The investigator determines the subject has poor compliance or any other factor precluding trial participation, including but not limited to conditions placing the subject at unacceptable risk or likely confounding study results.