A Phase 1 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of BL-M05D1 in Subjects With Advanced or Metastatic Solid Tumors

This is a multicenter Phase 1, open-label study to evaluate the safety, tolerability, pharmacokinetic profile, and initial efficacy of BL-M05D1 in subjects with unresectable locally advanced or metastatic solid tumors that are known to potentially express CLDN18.2 as defined below that have recurred or progressed on at least 1 line of prior systemic therapy (including adjuvant/neoadjuvant), have no other standard of care options, and have no available curative options.

This study will be conducted in three parts (dose escalation, dose finding and dose expansion). Subjects will be dosed on Day 1 on a continuous 21-day treatment cycle.

Sex: ALL
Minimum Age: 18 Years
Maximum Age: 85 Years
Healthy Volunteers: No
Age Groups: ADULT, OLDER_ADULT

Inclusion Criteria:

1. Signed the informed consent form 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 solid tumor(s) that are known to potentially express CLDN18.2 as defined below that have recurred or progressed on at least 1 line of prior systemic therapy (including adjuvant/neoadjuvant), have no other standard of care options, and have no available curative options, including:

1. Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (AC): Subjects with CLDN18.2, human epidermal growth factor receptor 2 (HER2), PD-L1 and/or microsatellite instability high (MSI-H)/ mismatch repair deficiency (dMMR) positive tumors must have received targeted treatment in their prior lines of therapy.
2. Pancreatic ductal AC (PDAC): Subjects may enter screening prior to completing the first line of standard therapy.
3. Esophageal AC (EAC): Subjects with HER2, PD-L1 and/or MSI-H/dMMR positive tumors must have received targeted treatment in their prior lines of therapy.
4. Biliary tract cancers (BTCs): Subjects with HER2 overexpression, NTRK fusions, KRAS mutations, IDH1 mutations, FGFR2 fusions, BRAF mutations and/or MSI-H/dMMR positive tumors must have received targeted treatment in their prior lines of therapy.
5. Other solid tumors not specified above may be included IF they have documented CLDN18.2 expression by IHC (1+). As applicable per standard of care, subjects with HER2 and/or PD-L1 positive tumors must have received targeted treatment in their prior lines of therapy, and subjects with MSI-H or dMMR positive tumors must have received immune checkpoint inhibitor.
5. Agree to provide most recent existing tumor samples (formalin-fixed paraffin-embedded [FFPE] tissue block or slides) from primary or metastatic sites (see details in Section 7.1.1) for tissue-based evaluation of CLDN18.2 expression. A fresh biopsy is required if no archival/FFPE block or slides are available. Re-biopsy is recommended if the subject previously received a CLDN18.2-directed treatment.
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 the National Cancer Institute (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) ≥1.5×109/L, platelet count (PLT) ≥100×109/L, hemoglobin (Hb) ≥9.0 g/dL (blood transfusion, platelet transfusion, erythropoietin, hematopoiesis agents, and granulocyte-colony stimulating factor [G-CSF] use are not allowed 1 week prior to screening)
2. Hepatic function: Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN) (≤3×ULN for subjects with Gilbert’s syndrome or liver metastasis at baseline), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) without liver metastasis ≤3.0×ULN, AST and ALT with liver metastasis ≤5.0×ULN NOTE: For patients with Gilbert’s syndrome, conjugated bilirubin ≤1.5×ULN and TBIL 45 years old in the absence of other biological or physiological causes. In addition, females 40 mIU/mL to confirm menopause.

Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

Exclusion Criteria:

1. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, 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; 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 heart disease, such as symptomatic congestive heart failure (CHF) ≥ Grade 2 (CTCAE v5.0), New York Heart Association (NYHA) ≥ Grade 2 heart failure at any time, or history of myocardial infarction or unstable angina pectoris within 6 months before enrollment
3. Subjects with prolonged QT interval corrected ([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. Subjects with well-controlled type 1 diabetes, hypothyroidism, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis) are permitted. For autoimmune conditions that are active but stable and low grade on systemic therapy, discussion with the medical monitor is required prior to screening
5. Subjects with other prior 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 prior to screening
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 with advanced or clinically significant lung diseases, such as poorly controlled chronic obstructive pulmonary disease and asthma, restrictive lung disease, pulmonary hypertension, etc.
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 or transient ischemic attack (TIA) within 6 months before enrollment
10. Subjects with a thromboembolic event (eg, deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months before enrollment except for those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before enrollment
11. 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/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
15. Subjects who have received treatment with anthracyclines with a cumulative dose exceeding 360 mg/m2
16. Subjects with known human immunodeficiency virus (HIV) infection (HIV antibody positive). Subjects are allowed to participate if all 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 enrollment with projected continuation of ART as clinically indicated while on the study.
17. Subjects with known active hepatitis B virus (HBV) infection (positive HBsAg test). Subjects with a chronic inactive HBV infection are eligible if all the following criteria are met:

1. Have an HBV DNA viral load < 500 IU/mL;
2. Have normal AST and ALT, OR if liver metastasis is present, have AST and ALT the lower limit of detection). Subjects with a positive anti-HCV antibody are eligible only if quantitative polymerase chain reaction (PCR) is negative for HCV RNA
19. Subjects with known active tuberculosis
20. 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
21. Subjects who are pregnant, breastfeeding, or planning to become pregnant during the study
22. Other conditions that the investigator believes are not suitable for participating in this clinical trial.