Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of BL-M05D1 in Subjects With Solid Tumors

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

The objective of this study is 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, including but not limited to gastric and gastroesophageal junction adenocarcinoma (G/GEJ AC), esophageal AC (EAC), pancreatic ductal AC (PDAC), and biliary tract cancer (BTC). Participants must 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 of a continuous 21-day treatment cycle.

Inclusion Criteria:

1. Signed the informed consent form voluntarily and agreed to follow the program requirements.

2. Age ≥18 years.

3. Life expectancy of ≥3 months.

4. Dose Escalation and Dose Finding (Parts 1 and 2): 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 (refer to Section 6.3.1), have no other standard of care options, and have no available curative options, including the following:

   1. Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (AC): Participants with CLDN18.2, 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): Participants who have received at least 1 line of standard therapy.
   3. Esophageal AC (EAC): Participants 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): Participants 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, participants with HER2 and/or PD-L1 positive tumors must have received targeted treatment in their prior lines of therapy, and participants 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 participant previously received a CLDN18.2-directed treatment.

6. At least 1 measurable lesion based on RECIST v1.1.

7. 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.

   Exceptions: Alopecia and endocrinopathies controlled by replacement therapy must be Grade ≤2.

9. No serious cardiac dysfunction, left ventricular ejection fraction ≥50%.

10. Adequate organ function before enrollment, defined as follows:

    1. Marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet (PLT) count ≥100×109/L, hemoglobin (Hb) ≥9.0 g/dL (blood transfusion, platelet transfusion, erythropoietin (EPO), hematopoiesis agents, and 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 participants 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 participants with Gilbert's syndrome, conjugated bilirubin ≤1.5 × ULN and TBIL <3.0 × ULN in the absence of liver metastases.

    3. Renal function: creatinine clearance (CrCl) ≥60 mL/min (Cockcroft-Gault equation) or estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation).

11. Coagulation parameters: International normalized ratio (INR) ≤1.5 × ULN, and activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless receiving anticoagulation therapy with prothrombin time and aPTT levels within the intended therapeutic range.

12. Sexually active fertile participants and their partners must agree to use highly effective methods of contraception (defined in Section 17.5 [Appendix E]) during the course of the study and after the last dose of study treatment (7 months for women and 4 months for men). An additional contraceptive method, such as a barrier method (eg, condom), is recommended.

13. Individuals of childbearing potential (IOCBP) must have a negative serum pregnancy test at screening and must be nonlactating. Female participants are considered IOCBP 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.

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

14. All participants must be willing to receive prophylactic G-CSF during their time on study (see Section 6.3.4.5).

    Additional Inclusion Criteria for Dose Optimization (Part 3)

15. PDAC Expansion Arm: Participants who have received at least 1 line of standard therapy and no more than 2 lines of systemic therapy (refer to Section 6.3.1).

    Note: Participants who have received prior treatment with a CLDN18.2-directed treatment must be able and willing to provide tissue sample obtained following treatment with anti-CLDN18.2 agent.

16. Basket Expansion Arm: 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 in the advanced or metastatic setting (refer to Section 6.3.1).

    1. G/GEJ AC: Participants with CLDN18.2, HER2, PD-L1, and/or MSI-H/dMMR positive tumors must have received targeted treatment in their prior lines of therapy.
    2. G/GEJ AC and BTCs: Participants who have received prior treatment with an anti-CLDN18.2 antibody must be able and willing to provide tissue sample obtained following treatment with anti-CLDN18.2 agent.
    3. BTCs: Participants 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.

Exclusion Criteria:

1. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, targeted therapy (including small-molecule inhibitor of tyrosine kinase), or other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration of study drug; major surgery within 4 weeks prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration.

2. Participants 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. Participants 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, or Hashimoto's thyroiditis..

   Exception: Participants with skin diseases that do not require systemic treatment (such as vitiligo, psoriasis); well-controlled type 1 diabetes; or hypothyroidism are permitted.

   Note: For autoimmune conditions that are active but stable, low grade, and on systemic therapy, discussion with the medical monitor is required prior to screening.

5. Participants with other prior malignancies.

   Exceptions: 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. Participants with advanced or clinically significant lung diseases such as poorly controlled chronic obstructive pulmonary disease (COPD) or asthma, restrictive lung disease, or pulmonary hypertension.

7. Participants who have a history of noninfectious interstitial lung disease (ILD)/pneumonitis that required treatment with steroids or have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

8. Participants with stroke or transient ischemic attack (TIA) within 6 months before enrollment.

9. Participants with a thromboembolic event (eg, deep vein thrombosis, pulmonary embolism) within 6 months before enrollment.

   Exception: Those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before enrollment may participate.

10. Participants with primary tumors in the central nervous system (CNS), or active or untreated CNS metastases and/or carcinomatous meningitis.

    Exception: Participants with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks, have no evidence of new or enlarging brain metastases, and have no requirements for corticosteroids 14 days prior to dosing with the IP. Participants on low-dose corticosteroids (<10 mg prednisone or equivalent/day) may participate.

11. Participants with pre-existing Grade ≥2 peripheral neuropathy.

12. Participants who have a history of anaphylaxis or severe hypersensitivity to recombinant humanized antibodies, human-mouse chimeric antibodies, or any of the components of BL-M05D1.

13. Participants who are receiving treatment with systemic glucocorticoids >10 mg/day equivalent of prednisone.

    Exceptions:

    1. Treatment of COPD and infusion-related reactions (IRRs) is permitted.
    2. Treatment with low-dose glucocorticoids (≤10 mg/day equivalent of prednisone), including antiemetics, is permitted.
    3. The chronic use of topical, inhaled, and locally injected steroids is permitted.

14. Participants with known or suspected human immunodeficiency virus (HIV) infection (HIV antibody positive).

    Exceptions: Participants 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 acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 12 months prior to screening; and
    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.

15. Participants with known active hepatitis B virus (HBV) infection (positive hepatitis B surface antigen [HBsAg] test).

    Exceptions: Participants with a chronic inactive HBV infection are eligible if all the following criteria are met:

    1. HBV DNA viral load <500 IU/mL;
    2. normal AST and ALT, or if liver metastasis is present, AST and ALT <3 × ULN that are not attributed to HBV infection; and
    3. on antiviral treatment as clinically indicated.

16. Participants with known active hepatitis C virus (HCV) infection (HCV antibody positive and HCV-RNA > the lower limit of detection).

    Exception: Participants with a positive anti-HCV antibody are eligible only if quantitative polymerase chain reaction (qPCR) is negative for HCV-RNA.

17. Participants with known active tuberculosis.

18. Participants with active infections that require IV antibiotic, antiviral, or antifungal treatment, such as severe pneumonia, bacteremia, or sepsis, within 1 week prior to first dose of study treatment.

    Exception: Participants on stable oral antimicrobials with no clinical or laboratory evidence of active infection are eligible.

19. Participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

20. Other conditions that the investigator or sponsor believes are not suitable for participating in this clinical trial.

21. For Dose Optimization Only: Prior treatment with any topoisomerase inhibitor ADC.