A Phase 1 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BL-M17D1 in Subjects with HER2-Expressing or HER2-Mutant Advanced or Metastatic Solid Tumors

The objective of this study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of BL-M17D1 in patients with HER2-Expressing or HER2-Mutant Advanced or Metastatic Solid Tumors.

BL-M17D1-ST-101 is a multicenter, Phase 1 study evaluating the safety, tolerability, pharmacokinetic profile, and initial efficacy of BL-M17D1 in subjects with unresectable locally advanced or metastatic HER2-expressing or HER2-mutant solid tumors. This study will be conducted in three parts (dose escalation, dose finding and dose expansion). BL-M17D1 will be administered on Day 1 of a continuous 21-day treatment cycle.

Eligibility Criteria:
Inclusion Criteria:

1. Signed the informed consent voluntarily and agreed to follow the program requirements.
2. Age: ≥18 years
3. Has a life expectancy of ≥3 months
4. Has documented locally advanced or metastatic HER2-positive solid tumor(s) (IHC 1+ to 3+ or in situ hybridization \[ISH\] positive) or HER2-mutant tumor specimen not amenable to curative surgery or radiation and has received at least 2 for 7 months after the last dose of study treatment. An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
5. Agree to provide existing tumor samples (formalin-fixed paraffin-embedded \[FFPE\] tissue block or slides) from primary or metastatic sites obtained within 2 years or FFPE block from fresh biopsy for tissue-based IHC staining to centrally determine HER2 expression. If no archival tissue is available, a fresh tissue biopsy is highly encouraged but not mandatory.
6. Has at least one measurable lesion based on RECIST (Response Evaluation Criteria in Solid Tumors) V1.1
7. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1
8. 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 that must be Grade ≤2
9. Has no serious cardiac dysfunction, left ventricular ejection fraction ≥50%
10. Has adequate organ function before enrollment, defined as:

    1. Marrow function: Absolute neutrophil count (ANC) ≥1.2×109/L, platelet count ≥100×109/L, hemoglobin (Hb) ≥90 g/L
    2. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN (≤3×ULN for subjects with Gilbert's syndrome), AST and ALT without liver metastasis ≤2.5 ULN, AST and ALT with liver metastasis ≤5.0 ULN
    3. Renal function: Creatinine clearance ≥60 mL/minute (Cockcroft-Gault equation)
11. Coagulation parameters: International normalized ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (APTT) ≤1.5×ULN
12. Urine protein ≤2+ or ≤1000 mg/24 hours
13. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception 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.
14. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating.

Exclusion Criteria:

1. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other antitumor therapy within 2 weeks or 5 half-lives (whichever is longer) prior to the first administration; major surgery within 4 weeks prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration
2. Subjects with history of severe investigational product (IP). Patients on low dose corticosteroids (\<10 mg prednisone or equivalent/day) may participate
3. Subjects with prolonged QT interval (QTcF \>470 msec), complete left bundle branch block, Grade 3 atrioventricular block
4. 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)
5. Subjects with other prior or concurrent malignant tumors diagnosed within 5 years prior to the first administration considered to be in remission, with the following exceptions: basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ after radical resection, or other malignancy in which treatment does not interfere with the safety or efficacy assessment of the investigational product
6. Subjects with poorly controlled hypertension by two types of antihypertensive drugs (systolic blood pressure \>150 mmHg or diastolic blood pressure \>100 mmHg)
7. Subjects who have Grade 3 lung disease according to NCI CTCAE v5.0
8. 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
9. Subjects with stroke (including transient ischemic attack \[TIA\]), myocardial infarction, or other ischemic event or thromboembolic event (eg, deep vein thrombosis \[DVT\] or pulmonary embolism \[PE\]) within 6 months before randomization except for those with a diagnosis of DVT who are stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before randomization
10. Subjects with primary tumors in the central nervous system (CNS) and active or untreated CNS metastases and/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 dosing with the investigational product (IP). Patients on low dose corticosteroids (\<10 mg prednisone or equivalent day) may participate \< body\>
11. Subjects with pre-existing ≥Grade 2 peripheral neuropathy
12. Subjects who have a history of allergies to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of BL M17D1
13. 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 chronic use of topical, inhaled, and locally injected steroids is permitted
14. Subjects who have received treatment with anthracyclines with a cumulative dose exceeding 360 mg/m2
15. Known human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number \> the lower limit of detection) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA \> the lower limit of detection)
16. Subjects with active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc., that require use of intravenous antibiotics, antiviral drugs, or antifungal drugs within 2 weeks or two half-lives (whichever is longer) prior to first dose of study treatment
17. Participated in another clinical trial within 4 weeks or two half-lives (whichever is longer) prior to first dose of study treatment
18. Subjects who are pregnant or breastfeeding
19. Other conditions that the investigator or sponsor believes are not suitable for participating in this clinical trial.

heart disease, such as symptomatic congestive heart failure (CHF) ≥ Grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥ Grade 2 heart failure, history of transmural myocardial infarction, unstable angina pectoris, etc.