A Study of BL-M07D1 in Patients With a Variety of Solid Tumors Including Locally Advanced or Metastatic HER2-positive/Low-expressing Urinary and Gastrointestinal Tumors

Study Overview
=================
Brief Summary
-----------------
Phase Ib: Explore the safety and tolerability of BL-M07D1 to further define RP2D in a variety of solid tumors, including locally advanced or metastatic urinary and gastrointestinal tumors. Phase II: To explore the efficacy of BL-M07D1 in patients with a variety of solid tumors including locally advanced or metastatic HER2-positive/low-expressing urinary and gastrointestinal tumors.

Official Title
-----------------
A Phase Ib/II Clinical Study to Evaluate the Safety and Efficacy of BL-M07D1 for Injection in Patients With Locally Advanced or Metastatic HER2-positive/Low-expressing Urinary and Gastrointestinal Solid Tumors

Conditions
-----------------
Her2-positive/Low-expression Urinary and Digestive Tract Tumors

Intervention / Treatment
-----------------
* Drug: BL-M07D1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily signed informed consent, and follow the plan; No gender limit; Age: ≥18 years old; expected survival time ≥3 months; Patients with histologically and/or cytologically confirmed, unresectable, locally advanced or metastatic HER2-positive/low-expressing urinary and gastrointestinal solid tumors that have failed, are unavailable to, or are not currently suitable for standard therapy. Failure of standard therapy was defined as failure of platinum-based therapy for urothelial carcinoma and failure of standard therapy for biliary tract carcinoma). HER2 positive: IHC3 +, or IHC2 + positive and FISH; HER2 low expression: IHC2+ and FISH negative, or IHC1+; Agreed to provide primary tumors or metastases 2 years archive of tumor tissue samples or fresh tissue samples (detect HER2 protein expression in tumor pathological tissue, exploring study its correlation with BL - M07D1 effectiveness index); If the participants can't provide the tumor tissue samples, in accord with other cases, all criteria after researchers assess the can into the group; Must have at least one measurable lesion according to RECIST v1.1 definition; ECOG score 0 or 1; Always anti-tumor treatment toxicity has been restored to NCI - CTCAE v5.0 definition of grade 1 or less, hair loss, fatigue, pigmentation, stable after hormone replacement therapy of hypothyroidism, 2 levels of peripheral nerve toxicity after chemotherapy, except other criteria for the provisions); No severe cardiac dysfunction, left ventricular ejection fraction ≥50%; The level of organ function must meet the following requirements and meet the following standards: a) Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; B) the liver function: total bilirubin (TBIL 1.5 ULN) or less, no liver metastasis of AST and ALT are ULN 2.5 or less, with liver metastasis AST and ALT are 5.0 ULN or less; c) Renal 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; The urine protein + 2 or 1000 mg / 24 h or less or less; Albumin acuity 30 g/L; For premenopausal women with childbearing potential, a pregnancy test must be performed within 7 days before the initiation of 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: Antineoplastic therapy such as chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy (including small-molecule tyrosine kinase inhibitors) within 4 weeks or 5 half-life times (whichever is shorter) before the first dose; Mitomycin and nitrosoureas were administered within 6 weeks before the first dose; Oral fluorouracil drugs such as S-1, capecitabine, or palliative radiotherapy within 2 weeks before the first dose; Traditional Chinese medicine or Chinese patent medicine with anti-tumor indications within 2 weeks before the first administration; Prior treatment with an ADC drug containing a camptothecin derivative (topoisomerase I inhibitor) as a toxin; A history of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, third degree atrioventricular block, complete left bundle branch block, frequent and uncontrollable arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation, and ventricular flutter (except transient); prolonged QT interval at rest (QTc > 450 msec in men or QTc > 470 msec in women); acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first dose; patients with New York Heart Association (NYHA) functional class ≥II heart failure; Active autoimmune disease or inflammatory diseases, such as: systemic lupus erythematosus, systemic treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and hashimoto's thyroiditis, etc., with the exception of type I diabetes, only replacement therapy can control the hypothyroidism, no systemic treatment of skin disease (e.g., vitiligo, psoriasis); Patients with other malignant tumors within 5 years before the first administration, except those who have been cured skin squamous cell carcinoma, basal cell carcinoma, superficial bladder cancer, prostate/cervix/breast cancer in situ and so on are considered to be eligible for enrollment; Unstable deep vein thrombosis, arterial thrombosis, and pulmonary embolism requiring medical intervention within 6 months before screening; Infusion-related thrombosis was excluded; Patients with massive pleural, abdominal and pelvic effusion or pericardial effusion, or with obvious symptoms, or poorly controlled pleural, abdominal and pelvic effusion or pericardial effusion (poorly controlled was defined as requiring more than 2 times of puncture and drainage within one month); Hypertension poorly controlled by antihypertensive drugs (systolic BP &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg); The existing interstitial lung disease, drug-induced interstitial pneumonia, need steroid treatment of radioactive pneumonia, or has a history of these diseases; Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastases); Patients with a history of allergy to recombinant humanized antibody or human-mouse chimeric antibody or to any ingredient of BL-M07D1; Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT); Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower detection limit); Active hepatitis B virus infection (HBV-DNA copy number > 103 IU/ml) needs to be excluded; Patients with positive hepatitis B surface antigen (HBsAg), HBV-DNA copy number > central detection limit and ≤103 IU/ml should take anti-hepatitis B virus treatment for at least one week before the first dose; Active infections requiring systemic therapy, such as severe pneumonia, bacteremia, sepsis, etc; Had participated in another clinical trial within 4 weeks before the first dose (calculated from the time of the last dose); Pregnant or lactating women; Other circumstances considered by the investigator to be inappropriate for participation in the trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 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 received BL-M07D1 therapy in the first cycle (3 weeks). Participants who had a clinical benefit could receive additional cycles of additional treatment. Administration will be discontinued because of disease progression or intolerable toxicity or for other reasons. | Drug: BL-M07D1<br>* BL-M07D1 was administered by intravenous infusion every 3 weeks in 3-week cycles.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 24 months | 
| Phase II: 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 Ib/II: Treatment-Emergent Adverse Event (TEAE) | TEAE is defined as any adverse and unexpected change in body structure, function, or chemistry or any exacerbation of an existing condition (i.e., any clinically significant adverse change in frequency and/or intensity) during treatment. The type, frequency, and severity of TEAE will be assessed during treatment. | 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/II: 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/II: 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 II: Progression-free survival (PFS) | The PFS is defined as the time from the first dose of medication to disease progression or death, whichever occurred first. | Up to approximately 24 months | 
| Phase Ib/II: Cmax | Maximum serum concentration (Cmax) of BL-M07D1 will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: Tmax | Time to maximum serum concentration (Tmax) of BL-M07D1 will be investigated. | Up to approximately 24 months | 
| Phase Ib: T1/2 | Half-life (T1/2) of BL-M07D1 will be investigated. | Up to approximately 24 months | 
| Phase Ib: AUC0-t | Blood concentration - Area under time line. | Up to approximately 24 months | 
| Phase Ib: CL | The serum clearance rate of BL-M07D1 per unit time will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: Ctrough | Ctrough is defined as the lowest serum concentration of BL-M07D1 prior to the next dose will be administered. | Up to approximately 24 months | 
| Phase Ib/II: Anti-drug antibody (ADA) | Frequency and titer of anti-BL-M07D1 antibody (ADA) will be evaluated. | Up to approximately 24 months |