Overview

The objective of this study is to evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BL-M14D1 in Subjects with locally Advanced or Metastatic Small Cell Lung Cancer and Other Neuroendocrine Tumors

Eligibility

Inclusion Criteria:

1. Signed the informed consent form voluntarily and agreed to follow the trial requirements
2. Age ≥18 years
3. Subject weighs more than 40 kg
4. Has a life expectancy of ≥3 months
5. Has documented locally advanced or metastatic SCLC, large cell neuroendocrine cancer (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastrointestinal neuroendocrine tumors (GI-NET), Merkel cell carcinoma (MCC), or other neuroendocrine tumors (with neuroendocrine histology ≥10%) who have failed at least 1 line of standard therapy in the advanced/metastatic setting or are unable to receive standard treatment Notes: For SCLC, the subject must have failed at least 1 line of platinum therapy in the advanced/metastatic setting. No prior topoisomerase inhibitor-based antibody-drug conjugate (ADC) therapy is permitted
6. Agree to provide archival tumor samples (FFPE tissue block or slides) from primary or metastatic sites:
   1. In dose escalation and dose finding: archival tissue obtained within 2 years or FFPE block from fresh biopsy. If no archival tissue is available, a fresh tissue biopsy is required
   2. In dose expansion: an FFPE block from fresh biopsy or archival tissue (within 6 months) is required NOTE: If no archival tissue is available and, a fresh tissue biopsy is clinically contraindicated, please consult the sponsor.
7. Has at least one measurable lesion based on RECIST (Response Evaluation Criteria in

   Solid Tumors) V1.1

8. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1
9. Toxicity of previous antitumor therapy has returned to Grade ≤1 as defined by NCI CTCAE V5.0, except for alopecia and endocrinopathies controlled by replacement therapy
10. Has no serious cardiac dysfunction and left ventricular ejection fraction ≥50%
11. Has adequate organ function, defined as:
    1. Marrow function: Absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin (Hb) ≥9.0 g/dL (blood transfusion, platelet transfusion, erythropoietin (EPO), hematopoiesis agents (such as thrombopoietin [TPO]), and G-CSF use are not allowed 1 week prior to screening)
    2. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN (≤3×ULN for subjects with Gilbert's syndrome or liver metastasis at baseline), AST and ALT without liver metastasis ≤3.0×ULN, AST and ALT with liver metastasis ≤5.0×ULN
    3. Renal function: Creatinine (Cr) clearance ≥60 mL/minute (Cockcroft-Gault equation)
12. Coagulation parameters: International normalized ratio (INR) ≤1.5×ULN, and activated

    partial thromboplastin time (aPTT) ≤1.5×ULN, unless receiving anticoagulation therapy with PT and aPTT levels within the intended therapeutic range

13. Urine protein ≤2+ or ≤1000 mg/24 hours
14. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception (defined in Appendix D) during the course of the study and for 7 months after the last dose of study treatment. An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
15. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating. Female subjects are considered WOCBP unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman >45 years old in the absence of other biological or physiological causes. In addition, females <55 years old must have a serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause.

Exclusion Criteria:

1. Chemotherapy, biological therapy, immunotherapy, , targeted therapy (including small molecule inhibitor of tyrosine kinase), and other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration; radical radiotherapy, major surgery within 4 weeks prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; oral fluorouracil drugs such as tegafur, capecitabine, or palliative radiotherapy within 2 weeks prior to initial administration.
2. Subjects who have received prior topoisomerase inhibitor-based ADC therapy
3. Concomitant use of strong inhibitors and inducers of any CYP enzyme or transporter system within 2 weeks prior to the first administration and throughout all parts of the study
4. Subjects with history of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥Grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥Grade 2 heart failure at any time, history of myocardial infarction or unstable angina pectoris within 6 months before enrollment
5. Subjects with prolonged QT interval (QTcF >470 msec), complete left bundle branch block, Grade 3 atrioventricular block, or a history of additional risk factors for Torsades de Pointes (TdP; eg, heart failure as defined in Exclusion Criterion 4, chronic or recurrent hypokalemia that requires medical intervention, congenital long QT syndrome, family history of long QT syndrome) or any current concomitant medication known to prolong the QT/QTc interval or cause TdP
6. Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease and Hashimoto's thyroiditis, etc., except for type 1 diabetes, hypothyroidism that can be controlled by standard of care treatment, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis)
7. Subjects with other prior or concurrent malignancies except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ after adequate resection, or other malignancy treated with curative intent with a disease-free interval of at least 3 years
8. Subjects with poorly controlled hypertension by 2 types of antihypertensive drugs (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg)
9. Subjects with advanced/ clinically significant lung diseases, such as poorly controlled COPD and asthma, restrictive lung disease, pulmonary hypertension etc.
10. Subjects who have a history of noninfectious interstitial lung disease (ILD)/pneumonitis that required treatment with steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
11. Subjects with stroke or transient ischemic attack (TIA) within 6 months before screening
12. Subjects with a thromboembolic event (eg, deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months before screening except for those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before screening
13. Subjects with primary tumors in the central nervous system (CNS), active or untreated CNS metastases or carcinomatous meningitis should be excluded. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and have no evidence of new or enlarging brain metastases and no requirements for corticosteroids 14 days prior to screening.
14. Subjects with pre-existing Grade ≥2 peripheral neuropathy
15. Subjects who have a history of anaphylaxis or severe hypersensitivity to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of BL-M14D1
16. Previous organ transplantation or allogeneic hematopoietic stem cell transplantation
17. Subjects who are receiving treatment with systemic glucocorticoids >10 mg/day equivalent of prednisone, except for the treatment of chronic obstructive pulmonary disease, antiemetic, infusion reactions; however, treatment with low dose glucocorticoids (≤10 mg/day equivalent of prednisone) is permitted. The use of topical, inhaled, and locally injected steroids is permitted
18. Subjects who have received treatment with anthracyclines with a cumulative dose exceeding 360 mg/m2
19. Subjects with known human immunodeficiency virus infection (HIV Ab positive). Subjects are allowed to participate if all of the following criteria are met: (1) Undetectable HIV RNA and CD4 count ≥350 cells/μL at Screening, (2) No AIDS-defining opportunistic infection within 12 months prior to screening, (3) On stable antiretroviral therapy (ART) for at least 4 weeks prior to Screening with projected continuation of ART as clinically indicated while on the study
20. Subjects with active hepatitis B virus (HBV) infection (positive HBsAg test). Subjects with chronic inactive HBV infection are eligible if they meet all of the following criteria:
    1. Have a HBV DNA viral load ≤ 500 IU/mL
    2. Have normal AST and ALT, OR if liver metastasis is present, has AST and ALT < 3 × ULN which are not attributed to HBV infection
    3. Are on antiviral treatment, as clinically indicated.
21. Subjects with active hepatitis C virus (HCV) infection (HCV antibody positive and

    HCV RNA > the lower limit of detection). Subjects with a positive anti-HCV antibody are eligible only if PCR is negative for HCV RNA

22. Subjects with active or latent tuberculosis
23. Subjects with active infections requiring IV antibiotic, antiviral, or antifungal treatment, such as severe pneumonia, bacteremia, sepsis, etc., within 1 week prior to first dose of study treatment. Subjects on stable oral antimicrobials with no clinical or laboratory evidence of active infection are eligible.
24. Participated in another clinical trial within 4 weeks prior to first dose of study treatment
25. Subjects who are pregnant or breastfeeding, or planning to become pregnant during the study
26. Other conditions that the Investigator or Sponsor believes are not suitable for participating in this clinical trial