Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, Efficacy of BL-M11D1 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

The objective of this study to evaluate the safety, tolerability, pharmacokinetic profile, and preliminary efficacy of BL-M11D1 in patients with relapsed/refractory acute myeloid leukemia.

BL-M11D1-HM-101 is a multi-center, Phase 1 study to evaluate the safety, tolerability, pharmacokinetic profile, and preliminary efficacy of BL-M11D1 in patients with relapsed/refractory acute myeloid leukemia.

This study will be conducted in two parts (dose escalation, and dose finding). Cohort will be dosed on Day 1 of a continuous 28-day treatment cycle. The cohort has different dose groups.

Eligibility Criteria:
Inclusion Criteria:

1. Signed the informed consent
2. Age ≥18 years
3. Has a life expectancy of ≥3 months
4. Relapsed and/or refractory CD33-positive AML as determined by pathology review at the treating institution that has failed initial standard of care therapy. Diagnosis of primary AML or AML secondary to myelodysplastic syndromes. Relapsed or refractory status. CD33-positive as confirmed by local flow cytometry or cytology.
5. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2
6. Toxicity of previous anticancer 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
7. Has adequate liver and renal function before registration, defined as: a. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN (≤3×ULN for subjects with Gilbert's syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN b. Renal function: Creatinine clearance ≥50 mL/min (Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration \[CKD-Epi\], or Modification of Diet in Renal Disease Study \[MDRD\] equations)
8. 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
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating.

Exclusion Criteria:

1. Subjects with acute promyelocytic leukemia (APL) or chronic myelogenous leukemia in blast crisis (CML)
2. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy (including small molecule inhibitor of tyrosine kinase), and other anticancer therapy within 2 weeks or 5 half-lives (3 half-lives for antibodies) (whichever is longer) prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration, or palliative radiotherapy within 2 weeks prior to the first administration
3. 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, history of transmural myocardial infarction, unstable cardiac arrhythmias or angina pectoris, etc.
4. Subjects with prolonged QT interval (QTcF \>470 msec), complete left bundle branch block, Grade 3 atrioventricular block
5. 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 I diabetes, hypothyroidism that can be controlled only by standard of care treatment, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis)
6. Subjects with other prior or concurrent malignant tumors were diagnosed within 5 years prior to the first administration 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
7. Subjects with resistant and refractory hypertension or uncontrolled hypertension despite ≥3 different types of antihypertensive drugs (systolic blood pressure \>150 mmHg or diastolic blood pressure \>100 mmHg)
8. Subjects with active acute or chronic graft vs. host disease (aGVHD or cGVHD) should be excluded from this study. Subjects with GVHD who are receiving treatment with systemic glucocorticoids \>10 mg/day equivalent of prednisone should also be excluded from the study; however, treatment with low-dose glucocorticoids (≤10 mg/day equivalent of prednisone) is permitted
9. Subjects currently receiving immunosuppressive therapy should be excluded from this study.
10. Clinical evidence of disseminated intravascular coagulation (DIC). Smoldering low grade DIC is allowed after discussion with the sponsor
11. 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. Infusion set-related thrombosis is excluded
12. Subjects with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgment. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor
13. Subjects with pre-existing ≥Grade 2 peripheral neuropathy
14. Subjects with Grade ≥3 lung disease defined by CTCAE v5.0
15. 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
16. Subjects who have a history of allergies to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of BL-M11D1
17. 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), active cytomegalovirus (CMV) infection
18. Subjects with active, uncontrolled 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 prior to start of treatment
19. Received an investigational drug within 4 weeks, or two half-lives (whichever is longer) prior to first dose of study treatment
20. Subjects who are pregnant or breastfeeding
21. Other conditions that the investigator or sponsor believes are not suitable for participating in this clinical trial.