A Study of BL-B01D1 in Patients With Unresectable Locally Advanced or Metastatic Breast Cancer and Other Solid Tumors

Study Overview
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Brief Summary
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In this study, the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase II dose (RP2D), the preliminary efficacy, pharmacokinetic characteristics, and immunogenicity of BL-B01D1 will be investigated in patients with unresectable locally advanced or metastatic breast cancer and other solid tumors.

Detailed Description
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In phase Ia, the safety and tolerability of BL-B01D1 in patients with unresectable locally advanced or metastatic breast cancer and other solid tumors. investigated to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of BL-B01D1. In phase Ib, the safety and tolerability of BL-B01D1 at the phase Ia recommended dose will be further investigated, and recommended phase II dose (RP2D) for phase II clinical studies will be determined The preliminary efficacy, pharmacokinetic characteristics, and immunogenicity of BL-B01D1 in patients with locally advanced or metastatic solid tumors will be evaluated. EGFR and/or HER3 protein expression or gene amplification in tumor pathological tissues will be detected, and the expression of related ligand will be explored to study its correlation with the validity index of BL-B01D1, and the biomarkers will be optimized to further study the correlation between selected biomarkers and initial efficacy.

Official Title
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A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of BL-B01D1 in Patients With Unresectable Locally Advanced or Metastatic Breast Cancer and Other Solid Tumors

Conditions
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Breast Cancer, Solid Tumor

Intervention / Treatment
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* Drug: BL-B01D1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Sign the informed consent voluntarily and follow the program requirements; 2. No gender limitation; 3. Age: ≥18 years old and ≤75 years old (Stage Ia); ≥18 years old (Ib); 4. Expected survival time ≥3 months; 5. Failure or intolerance to standard treatment confirmed by histopathology and/or cytology or no standard treatment currently available or unresectable locally advanced or metastatic breast cancer and other solid tumors for which standard treatment is not available; 6. Agree to provide archived tumor tissue samples or fresh tissue samples of primary or metastatic tumor within 3 years; If subjects are unable to provide tumor tissue samples, they will be admitted after evaluation by the investigator if other admission criteria are met. 7. Must have at least one measurable lesion as defined by RECIST V1.1; 8. ECOG score of 0 or 1; 9. Toxicity from previous antitumor therapy has returned to level ≤1 as defined by NCI-CTCAE V5.0 10. No serious cardiac dysfunction, left ventricular ejection fraction ≥50%; 11. Organ function level must meet the following requirements and meet the following standards: A) Bone marrow function: absolute neutrophil count (ANC) ≥1.5×10^9/L, platelet count ≥100×10^9/L, hemoglobin ≥90 g/L; B) Liver function: total bilirubin (TBIL≤1.5 ULN), AST and ALT ≤2.5ULN in patients without liver metastasis, AST and ALT ≤5.0 ULN in patients with liver metastasis; C) Renal function: Creatinine (Cr) ≤1.5 ULN, or creatinine clearance (Ccr) ≥50 mL/min. 12. Coagulation function: International standardized ratio (INR) ≤1.5, and activated partial thrombin time (APTT) ≤1.5ULN; 13. Urinary protein ≤2+ or ≤1000mg/24h; 14. For premenopausal women who are likely to have children, a pregnancy test must be performed within 7 days of the start of treatment. Serum or urine pregnancy must be negative and must be non-lactation; All enrolled patients (male and female) should use adequate barrier contraception throughout the treatment cycle and 6 months after the end of treatment. Exclusion Criteria: 1. Prior treatment with ADC drugs using camptothecin derivatives (topoisomerase I inhibitors) as toxins; 2. Use of chemotherapy, biotherapy, immunotherapy, radical radiotherapy, major surgery (as defined by the investigator), targeted therapy (including small molecule tyrosine kinase inhibitors) and other antitumor therapies within 4 weeks or 5 half-lives, whichever is less, prior to initial dosing; Mitomycin and nitrosourea were administered within 6 weeks prior to initial administration; Fluorouracil oral agents such as ticio, capecitabine, oral endocrine therapy, or palliative radiotherapy within 2 weeks before initial administration; 3. History of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥2 (CTCAE 5.0), Heart failure (NYHA) ≥2, history of transmural myocardial infarction, unstable angina, etc 4. QT prolongation (male QTc > 450 msec or female QTc > 470 msec), complete left bundle branch block, III atrioventricular block; 5. Active autoimmune and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease and Hashimoto's thyroiditis, are excluded from type I sugars urinary diseases, hypothyroidism that can be controlled only by alternative therapy, skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis); 6. Other malignant tumors were diagnosed within 2 years prior to first administration, except for radical basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radical resected carcinoma in situ; 7. Hypertension poorly controlled by two antihypertensive medications (systolic blood pressure & GT; 150 mmHg or diastolic pressure & GT; 100 mmHg); 8. Lung disease defined as grade ≥2 according to CTCAE V5.0, and now defined according to RTOG/EORTC Grade ≥1 radiation pneumonia; Existing patients with interstitial lung disease (ILD); 9. Screening for unstable thrombotic events such as deep vein thrombosis, arterial thrombosis and pulmonary embolism requiring therapeutic intervention within the first 6 months; Infusion device-related thrombosis is excluded; 10. Primary central nervous system (CNS) malignancy; Patients with CNS metastasis who have failed local treatment (excluding asymptomatic BMS, or those with stable clinical symptoms and no steroid or other treatment for BMS for ≥28 days); 11. Patients with uncontrolled pleural and abdominal effusion with clinical symptoms, judged by the investigator to be unsuitable for inclusion; 12. Patients with a history of allergy to recombinant humanized antibody or human-mouse chimeric antibody or to any excipient component of BL-B01D1; 13. Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (ALLO-HSCT); 14. Cumulative dose of anthracyclines > 360 mg/m^2 in previous anthracyclines (new) adjuvant therapy 15. Positive human immunodeficiency virus antibody (HIVAb), active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number > 10^3IU/ml) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower limit of detection); 16. Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc. 17. Participated in another clinical trial within 4 weeks prior to initial administration (starting from the time of last administration); 18. Other conditions considered inappropriate for participation in this clinical trial 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: BL-B01D1<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?
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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 21 days after the first dose | 
| Phase Ib: phase II clinical studies (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 21 days after the first dose | 
| Phase Ia: Maximum tolerated dose (MTD) | In the dose escalation stage, MTD was selected as the highest dose whose DLT rate estimate was closest to the target DLT rate, but did not exceed the upper bound of the EQUIVALENT interval of DLT rate. | Up to 21 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-B01D1 . The type, frequency and severity of TEAE will be evaluated during the treatment of BL-B01D1 . | Up to approximately 24 months | 
| Cmax | Maximum serum concentration (Cmax) of BL-B01D1 will be investigated | Up to 21 days after the first dose | 
| Tmax | Time to maximum serum concentration (Tmax) of BL-B01D1 will be investigated | Up to 21 days after the first dose | 
| T1/2 | Half-life (T1/2) of BL-B01D1 will be investigated | Up to 21 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 21 days after the first dose | 
| Ctrough | Ctough is defined as the lowest serum concentration of BL-B01D1 prior to the next dose will be administered | Up to 21 days after the first dose | 
| ADA (anti-drug antibody） | The anti-drug antibody of BL-B01D1 | Up to approximately 24 months | 
| Nab (neutralizing antibody) | Neutralizing anti-drug antibodies produced by BL-B01D1 | Up to approximately 24 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| CL (Clearance) | CL in the serum of BL-B01D1 per unit of time will be investigated | Up to approximately 24 months |