A Study of BL-B01D1 in Patients With Multiple Solid Tumors, Including Locally Advanced or Metastatic Urinary System Tumors

Study Overview
=================
Brief Summary
-----------------
Phase IIa/IIb clinical study to evaluate the safety, tolerability, pharmacokinetics and efficacy of BL-B01D1 for injection in patients with multiple solid tumors such as locally advanced or metastatic urinary system tumors.

Detailed Description
-----------------
Phase IIa: To explore the safety and initial efficacy of BL-B01D1 in a variety of solid tumors such as locally advanced or metastatic urinary system tumors, and further determine RP2D. The preliminary efficacy, pharmacokinetic characteristics and immunogenicity of BL-B01D1 were evaluated. Phase IIb: To explore the efficacy of BL-B01D1 as a single agent RP2D obtained in a Phase IIa clinical study. To evaluate the safety and tolerability, pharmacokinetic characteristics and immunogenicity of BL-B01D1.

Official Title
-----------------
Phase IIa/IIb Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of BL-B01D1 for Injection in Patients With Multiple Solid Tumors, Including Locally Advanced or Metastatic Urinary System Tumors

Conditions
-----------------
Urinary System Tumor, Solid Tumor

Intervention / Treatment
-----------------
* Drug: BL-B01D1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign the informed consent voluntarily and follow the program requirements. No gender limitation. Age: ≥18 years and ≤75 years. Expected survival time ≥3 months. Locally advanced or metastatic urinary system tumors and other solid tumors that have been confirmed by histopathology and/or cytology to have failed or been intolerant to standard treatment or currently have no standard treatment; Intolerance refers to grade 3-4 adverse reactions after a patient has received standard treatment, and the patient refuses to continue the original treatment. Agree to provide archived tumor tissue samples (10 unstained sections (anti-slip) surgical specimens (4-5μm thickness) or fresh tissue samples from primary sites or metastases within 3 years. If subjects are unable to provide tumor tissue samples, they can be enrolled after investigator evaluation if other inclusion criteria are met. There must be at least one measurable lesion that meets the RECIST v1.1 definition. Physical condition score ECOG 0 or 1. The toxicity of previous antitumor therapy was restored to ≤ class 1 as defined by NCI-CTCAE v5.0(the investigators considered asymptomatic laboratory abnormalities such as elevated ALP, hyperuricemia, elevated blood glucose, etc., and toxicities that the investigators judged to be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, or decreased hemoglobin but ≥90g/L). No serious cardiac dysfunction, left ventricular ejection fraction ≥50%. The organ function level must meet the following requirements: a) bone marrow function: absolute neutrophilic granulocyte count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; b) Liver function: total bilirubin (TBIL≤1.5 ULN), AST and ALT ≤2.5 ULN in patients without liver metastasis, AST and ALT ≤5.0 ULN in patients with liver metastasis; c) Kidney function: creatinine (Cr) ≤1.5 ULN, or creatinine clearance (Ccr) ≥50 mL/min (according to Cockcroft and Gault formula). Coagulation function: International Normalized ratio (INR) ≤1.5, and activated partial thromboplastin time (APTT) ≤1.5ULN. A pregnancy test must be performed within 7 days prior to the start of treatment for premenopausal women who are likely to have children, serum or urine pregnancy tests must be negative and must be non-lactating; All enrolled patients (male or female) should take adequate barrier contraception throughout the treatment cycle and for 6 months after completion of treatment. Exclusion Criteria: Antitumor therapy such as chemotherapy, biotherapy, immunotherapy, radical radiotherapy, major surgery (as defined by the investigators), and targeted therapy (including small-molecule tyrosine kinase inhibitors) within 4 weeks prior to initial administration or within 5 half-lives, whichever is shorter; Mitomycin and nitrosourea were administered within 6 weeks before the first administration; Oral fluorouracil drugs such as Tizio, capecitabine, or palliative radiotherapy within 2 weeks before first administration; The duration of radiotherapy or surgery for brain metastases was 4 weeks. Have a history of severe cardiovascular and cerebrovascular diseases, including but not limited to: a. Have serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree III atrioventricular block, etc.; b. Prolonged QT interval at rest (QTc > 450 msec in men or 470 msec in women); c. Myocardial infarction, unstable angina, angioplasty or stenting, coronary/peripheral artery bypass grafting, class III or Ⅳ congestive heart failure defined by the New York Heart Association (NYHA), cerebrovascular accident, or transient ischemic attack occurred within 6 months prior to initial administration. Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel diseases, Hashimoto's thyroiditis, etc., except type I diabetes mellitus, hypothyroidism that can be controlled by alternative therapy alone, and skin diseases that do not require systemic treatment (e.g. Vitiligo, psoriasis). There are other malignancies that have progressed or require treatment within 5 years prior to initial administration, with the following exceptions: basal cell carcinoma of the skin after radical treatment, squamous cell carcinoma of the skin, superficial bladder carcinoma, carcinoma in situ after radical resection, such as carcinoma in situ of the breast, and prostate cancer; Remarks: Participants with localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and PSA < 10ng/mL (as measured) at the time of prostate cancer diagnosis were admitted to this study after radical treatment and without biochemical recurrence of prostate-specific antigen (PSA). Patients with interstitial lung disease (ILD), defined as ≥ grade 3 lung disease according to CTCAE v5.0. Unstable thrombotic events such as deep vein thrombosis, arterial thrombosis and pulmonary embolism requiring therapeutic intervention within the first 6 months of screening; Thrombus formation associated with infusion set is excluded. Patients with central nervous system (CNS) metastasis. But have received brain metastases (radiation or surgery; Patients with stable BMS with BMS < 10mm in length and diameter who had stopped radiotherapy and surgery 28 days before the first dose could be enrolled. Stable is defined as: a. The seizureless state persists for > 12 weeks with or without antiepileptic medication; b. Glucocorticoid use is not required; c. Two consecutive MRI scans (at least 4 weeks between scans) showed stable imaging status; d. Asymptomatic patients stable for more than 1 month after treatment. Chest, abdomen and pelvic effusion or pericardial effusion with symptoms or symptomatic treatment. Patients with a history of allergy to recombinant humanized antibody or mouse chimeric antibody or to any excipients of BL-B01D1. Previous recipients of organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT). During previous treatment with anthracyclines, the equivalent cumulative dose of doxorubicin was greater than 360 mg/m2. Positive human immunodeficiency virus antibody (HIVAb), active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number > 103 IU/ml) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower limit of detection). Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, septicemia, etc. Other conditions deemed unsuitable for participation in this clinical trial by the investigator.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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-B01D1 as intravenous infusion for the first cycle (3 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-B01D1<br>* Administration by intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase IIa: 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-B01D1. | Up to approximately 24 months | 
| Phase IIb: 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase IIa/IIb: 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-B01D1. The type, frequency and severity of TEAE will be evaluated during the treatment of BL-B01D1. | Up to approximately 24 months | 
| Phase IIa: 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 IIb: Progression-free survival (PFS) | The PFS is defined as the time from the participant's first dose of BL-B01D1 to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase IIa/IIb: 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 IIa/IIb: 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 | 
| Phase IIa/IIb: Cmax | Maximum serum concentration (Cmax) of BL-B01D1 will be investigated. | Up to approximately 24 months | 
| Phase IIa/IIb: Tmax | Time to maximum serum concentration (Tmax) of BL-B01D1 will be investigated. | Up to approximately 24 months | 
| Phase IIa: T1/2 | Half-life (T1/2) of BL-B01D1 will be investigated. | Up to approximately 24 months | 
| Phase IIa: AUC0-t | Blood concentration - Area under time line. | Up to approximately 24 months | 
| Phase IIa: CL | To study the serum clearance rate of BL-B01D1 per unit time. | Up to approximately 24 months | 
| Phase IIa/IIb: Ctrough | Ctrough is defined as the lowest serum concentration of BL-B01D1 prior to the next dose will be administered. | Up to approximately 24 months | 
| Phase IIa/IIb: Anti-drug antibody (ADA) | Frequency and titer of anti-BL-B01D1 antibody (ADA) will be evaluated. | Up to approximately 24 months |