A Study of BL-M07D1 in Patients With HER2-mutated, Locally Advanced or Metastatic Non-small-cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
This phase Ib/II study is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of injectable BL-M07D1 in patients with HER2-mutated, locally advanced or metastatic non-small cell lung cancer.

Official Title
-----------------
A Phase Ib/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of BL-M07D1 for Injection in Patients With HER2 Mutated, Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Non-small Cell Lung Cancer

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


Participation Criteria
=================
Eligibility Criteria
-----------------
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. Histologically or cytologically confirmed, unresectable locally advanced or metastatic non-small cell lung cancer (stage IIIB/IV according to the UICC/AJCC 8th Edition), which is considered to be unresectable by the investigator's assessment. Confirmed known HER2-sensitive mutations, investigator-confirmed previous testing results, and trial site laboratory testing results were acceptable. Patients in the advanced stage who had received platinum-based chemotherapy and immunotherapy concurrent or sequential therapy were unable to tolerate standard treatment or had disease progression during or after treatment. Consent to provide archived tumor tissue or fresh tissue samples from primary or metastatic sites within 2 years for biomarker testing; Participants who were unable to provide tumor tissue samples could be enrolled if they met other inclusion and exclusion criteria after evaluation by investigators. Must have at least one measurable lesion according to RECIST v1.1 definition. ECOG score 0 or 1. 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 investigators, such as elevated alkaline phosphatase, hyperuricemia, and hyperglycemia; The toxicity was excluded if the investigators judged that there was no safety risk, such as alopecia, pigmentation, and grade 2 peripheral neurotoxicity). No severe cardiac dysfunction, left ventricular ejection fraction ≥50%. Provided that no blood transfusions and no use of any cell growth factors and/or platelet-raising agents are allowed for 14 days prior to the screening period, the level of organ function must meet the following criteria: Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; 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 and albumin ≥30 g/L; 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. Urine protein ≤2+ or ≤1000mg/24h. For premenopausal women with childbearing potential, a pregnancy test must be performed within 7 days before the start 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. Presence of other gene mutations for targeted drug therapy. 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 or 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 be controlled only by replacement therapy, and skin diseases without systemic treatment (such as vitiligo and 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 poorly controlled pericardial effusion, pleural effusion, peritoneal effusion, or pelvic effusion with clinical symptoms were judged by the investigator to be ineligible for enrollment. Hypertension poorly controlled by antihypertensive drugs (systolic BP &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg). Current interstitial lung disease, drug-induced interstitial pneumonia, radiation pneumonitis requiring steroid therapy, or a history of these diseases. Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastases). Patients who had received treatment for brain metastases (radiotherapy or surgery; Patients with stable brain metastases who had stopped radiotherapy or surgery 28 days before the first dose were eligible. Patients with cancerous meningitis (meningeal metastasis) were excluded even if they were treated and judged to be stable. Stable disease was defined as being asymptomatic, in stable condition, and not requiring steroid therapy for more than 4 weeks before starting study treatment. 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, active hepatitis B virus infection (HBV-DNA copy number > lower detection limit) or active hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower detection limit). 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
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: BL-M07D1<br>Participants receive BL-M07D1 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-M07D1<br>* Administration by intravenous infusion<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 of BL-M07D1. | Up to 21 days after the first dose | 
| 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 |
| --- | --- | --- |
| 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-M07D1. The type, frequency and severity of TEAE will be evaluated during the treatment of BL-M07D1. | 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 | 
| 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-M07D1 to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Cmax | Maximum serum concentration (Cmax) of BL-M07D1 will be investigated. | Up to 21 days after the first dose | 
| Tmax | Time to maximum serum concentration (Tmax) of BL-M07D1 will be investigated. | Up to 21 days after the first dose | 
| Ctrough | Ctrough is defined as the lowest serum concentration of BL-M07D1 prior to the next dose will be administered. | Up to 21 days after the first dose | 
| ADA (anti-drug antibody) | Frequency of anti-BL-M07D1 antibody (ADA) will be investigated. | Up to approximately 24 months |