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

Korábbi kezelés

• 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.
• 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.
• 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.
• 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.
• Participants with stroke or transient ischemic attack (TIA) within 6 months before enrollment.
• 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.
• 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.
• Participants who are receiving treatment with systemic glucocorticoids >10 mg/day equivalent of prednisone.
  • Exceptions:
  • Treatment of COPD and infusion-related reactions (IRRs) is permitted.
  • Treatment with low-dose glucocorticoids (≤10 mg/day equivalent of prednisone), including antiemetics, is permitted.
  • The chronic use of topical, inhaled, and locally injected steroids is permitted.
• For Dose Optimization Only: Prior treatment with any topoisomerase inhibitor ADC.

Más betegség

• 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.
• 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.
• 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.
• 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.
• Participants with known active tuberculosis.
• Other conditions that the investigator or sponsor believes are not suitable for participating in this clinical trial.

Laborértékek

• Participants with prolonged QT interval corrected (QTcF) >470 msec, complete left bundle branch block, Grade 3 atrioventricular block.
• 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:
  • undetectable HIV RNA and CD4 count ≥350 cells/μL at screening;
  • no acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 12 months prior to screening; and
  • 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.
• 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:
  • HBV DNA viral load <500 IU/mL;
  • normal AST and ALT, or if liver metastasis is present, AST and ALT <3 × ULN that are not attributed to HBV infection; and
  • on antiviral treatment as clinically indicated.
• 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.

Egyéb

• Participants with pre-existing Grade ≥2 peripheral neuropathy.
• Participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

• Signed the informed consent form voluntarily and agreed to follow the program requirements.
• Age ≥18 years.
• Life expectancy of ≥3 months.
• 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:
  • 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.
  • Pancreatic ductal AC (PDAC): Participants who have received at least 1 line of standard therapy.
  • 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.
  • 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.
  • 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.
• 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.
• At least 1 measurable lesion based on RECIST v1.1.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.
• 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.
• No serious cardiac dysfunction, left ventricular ejection fraction ≥50%.
• Adequate organ function before enrollment, defined as follows:
  • 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).
  • 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.
  • 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).
• 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.
• 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.
• 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.
• 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)
• 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.
• 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).
  • 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.
  • 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.
  • 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.