A Study of BL-M11D1 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Ia: To observe the safety and tolerability of BL-M11D1 in patients with relapsed/refractory acute myeloid leukemia to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of BL-M11D1. Ib: Further observe the safety and tolerability of BL-M11D1 at the recommended dose in phase Ia to determine the recommended dose in phase II clinical study (RP2D).

Official Title
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A Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of BL-M11D1 in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients

Conditions
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Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Intervention / Treatment
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* Drug: BL-M11D1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily sign the informed consent and follow the requirements of the protocol. No gender limit. Age: ≥18 years old and ≤75 years old. expected survival time ≥3 months. Relapsed/refractory acute myeloid leukemia (AML) confirmed by histopathology and/or cytology;Patients who met the following criteria were defined as relapsed/refractory AML, including: newly diagnosed patients who failed to respond to 2 courses of standard regimens; Patients who relapsed within 12 months after complete remission after consolidation and intensive therapy; Patients relapsed after 12 months but failed to respond to conventional chemotherapy; Patients with two or more recurrences; Patients with persistent extramedullary leukemia and bone marrow blasts ≥5%; Investigator-assessed patients with relapsed or refractory acute myeloid leukemia who were not or were ineligible for/intolerant of other therapies. ECOG ≤2. Toxicity of previous antineoplastic therapy has returned to grade 1 or less as defined by NCI-CTCAE v5.0 (except for asymptomatic laboratory abnormalities considered by the investigator, such as elevated alkaline phosphatase, hyperuricemia, elevated serum amylase/lipase, and elevated blood glucose; The exception was toxicity that was judged by the investigator to be not a safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism that was stable with hormone replacement therapy). The level of organ function within 7 days before the first dose meets the following requirements and meets the following criteria: Liver function: Total bilirubin ≤1.5 ULN (Gilbert's syndrome ≤3 ULN), transaminase (AST/ALT) ≤2.5 ULN (subjects with liver tumor invasive changes ≤5.0 ULN), and/or alkaline phosphatase ≤5 ULN without correction with liver-protective drugs within 7 days before screening; renal function: creatinine (Cr) ≤1.5 ULN or creatinine clearance (Ccr) ≥50 mL/min (according to the center's calculation criteria); coagulation function: international normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5ULN; proteinuria ≤2+ or ≤1000mg/24h. For premenopausal women with childbearing potential, pregnancy tests must be performed within 7 days before starting treatment, serum/urine pregnancy must be negative, and must be non-lactating; All enrolled patients (male or female) were advised to use adequate barrier contraception throughout the treatment cycle and for 6 months after the end of treatment. Exclusion Criteria: Acute promyelocytic leukemia, acute transformation of chronic myeloid leukemia. Antineoplastic therapy, including chemotherapy, biologic therapy, immunotherapy, definitive radiotherapy, major surgery (investigator-defined), or targeted therapy (including small-molecule tyrosine kinase inhibitors), has been administered within 4 weeks or 5 half-life cycles (whichever is shorter) before the first dose; Or palliative radiotherapy within 2 weeks before the first dose. History of severe heart disease, such as left ventricular ejection fraction < 50%, history of symptomatic congestive heart failure (CHF) ≥ grade 2 (CTCAE v5.0), New York Heart Association (NYHA) ≥ grade 2 heart failure, history of myocardial infarction, unstable angina, etc. Prolonged QT interval (QTc > 450 msec in men or QTc > 470 msec in women), complete left bundle branch block, and III degree atrioventricular block. Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory intestinal diseases and Hashimoto's thyroiditis, etc., excluding type I diabetes mellitus, hypothyroidism that can only be controlled by replacement therapy, and skin diseases without systemic treatment (such as vitiligo and psoriasis). Other malignancies diagnosed within 5 years before the first dose, except for radical basal cell carcinoma, squamous cell carcinoma, and/or radical resection carcinoma in situ. Poorly controlled hypertension (systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg). Patients with pulmonary disease grade ≥3 defined by CTCAE v5.0, current or previous interstitial lung disease (ILD). Patients with central nervous system involvement. Patients with a history of allergy to recombinant humanized antibody or human-mouse chimeric antibody or to any of the ingredients of BL-M11D1. Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Human immunodeficiency virus (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBsAg positive; HBcAb positive and HBV-DNA copy number > lower detection limit) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower detection limit). Active infection requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc. Presence of pleural, abdominal, pelvic or pericardial effusion with clinical symptoms or requiring repeated drainage. Had participated in another clinical trial within 4 weeks before the first dose (calculated from the time of last dose). Pregnant or lactating women. Other conditions for participation in the trial were not considered appropriate by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>Participants receive BL-M11D1 as intravenous infusion for the first cycle (4 weeks). Participants with clinical benefit could receive additional treatment for more cycles. The administration will be terminated because of disease progression or intolerable toxicity occurring or other reasons. | Drug: BL-M11D1<br>* Administration by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ia: Dose limiting toxicity (DLT) | DLTs are assessed according to NCI-CTCAE v5.0 during the first cycle and defined as occurrence of any of the toxicities in DLT definition if judged by the investigator to be possibly, probably or definitely related to study drug administration. | Up to 28 days after the first dose | 
| Phase Ia: Maximum tolerated dose (MTD) | MTD is defined as the highest dose level at which no more than 1 in 6 participants experienced a DLT during the first cycle . | Up to 28 days after the first dose | 
| Phase Ib: Recommended Phase II Dose (RP2D) | The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for phase II study, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study of BL-M11D1. | Up to 28 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Emergent Adverse Event (TEAE) | TEAE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally emerging, or any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition during the treatment of BL-M11D1. The type, frequency and severity of TEAE will be evaluated during the treatment of BL-M11D1. | Up to approximately 24 months | 
| Cmax | Maximum serum concentration (Cmax) of BL-M11D1 will be investigated. | Up to 28 days after the first dose | 
| Tmax | Time to maximum serum concentration (Tmax) of BL-M11D1 will be investigated. | Up to 28 days after the first dose | 
| T1/2 | Half-life (T1/2) of BL-M11D1 will be investigated. | Up to 28 days after the first dose | 
| AUC0-t | AUC0-t is defined as area under the serum concentration-time curve from time 0 to the time of the last measurable concentration. | Up to 28 days after the first dose | 
| CL (Clearance) | CL in the serum of BL-M11D1 per unit of time will be investigated. | Up to 28 days after the first dose | 
| Ctrough | Ctough is defined as the lowest serum concentration of BL-M11D1 prior to the next dose will be administered. | Up to 28 days after the first dose | 
| ADA (anti-drug antibody) | ADA of BL-M11D1 will be evaluated. | Up to approximately 24 months | 
| Phase Ib: Objective Response Rate (ORR) | ORR is defined as the percentage of participants, who has a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experiences a confirmed CR or PR is according to RECIST 1.1. | Up to approximately 24 months | 
| Phase Ib: Disease Control Rate (DCR) | The DCR is defined as the percentage of participants who has a CR, PR, or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD]). | Up to approximately 24 months | 
| Phase Ib: Duration of Response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months |