A Study Comparing BL-B01D1 With Physician's Choice of Chemotherapy in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma

Study Overview
=================
Brief Summary
-----------------
A phase III, randomized, open-label, multicenter study to evaluate the efficacy and safety of BL-B01D1 in patients with recurrent or metastatic nasopharyngeal carcinoma who had failed at least two lines of platinum-based chemotherapy after receiving PD-1/PD-L1 monoclonal antibody as the last line of therapy.

Detailed Description
-----------------
Primary objective: To evaluate BICR-based objective response rate (ORR) and overall survival (OS) benefit of BL-B01D1 versus physician's choice of chemotherapy.

Official Title
-----------------
A Phase III Randomized Controlled Trial to Compare BL-B01D1 With Physician's Choice of Chemotherapy (Last Line) in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma (NPC) Previously Treated With PD-1/PD-L1 Monoclonal Antibody and at Least Two Lines of Chemotherapy (at Least One Line of Platinum-based Chemotherapy)

Conditions
-----------------
Nasopharyngeal Carcinoma

Intervention / Treatment
-----------------
* Drug: BL-B01D1
* Drug: capecitabine
* Drug: gemcitabine
* Drug: docetaxel


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. expected survival time ≥3 months. Patients with histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma treated with PD-1/PD-L1 monoclonal antibody after failure of at least two lines of chemotherapy (at least one line of platinum-based). Patients who are suitable for the final line treatment with the control chemotherapy drugs specified in this protocol. Must have at least one measurable lesion according to RECIST v1.1 definition; If a single measurable lesion is present, baseline imaging of the lesion should not be performed until at least 14 days after biopsy has been performed, if biopsy has been performed; If the target lesion at the previous radiotherapy site was the only measurable lesion, investigators were required to provide pre-and post-imaging data showing significant progression of the lesion to confirm definite progression, at least 3 months before the end of radiotherapy. ECOG 0 or 1. Toxicity from previous antineoplastic therapy has returned to grade 1 or less as defined in NCI-CTCAE v5.0 (except alopecia, fatigue, hyperpigmentation, hormone-replacement stable hypothyroidism, grade 2 peripheral neurotoxicity after chemotherapy, or other eligibility criteria). No severe cardiac dysfunction, left ventricular ejection fraction ≥50%. No blood transfusion, no use of cell growth factors and/or platelet-raising agents within 14 days prior to the first dose of study drug, and organ function levels that meet the following criteria: Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥100 g/L; Liver function: total bilirubin ≤1.5×ULN (total bilirubin ≤3×ULN in subjects with Gilbert's syndrome or liver metastasis), AST and ALT ≤2.5×ULN in patients without liver metastasis, AST and ALT ≤5.0×ULN in patients with liver metastasis; 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)≤1.5×ULN. Urine protein ≤2+ or < 1000mg/24h. For premenopausal women with childbearing potential, a pregnancy test must be performed within 7 days before the initiation of treatment, serum 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: Chemotherapy, biotherapy, immunotherapy, definitive radiotherapy, major surgery, or large area radiotherapy (more than 30% bone marrow area or too large area irradiation) administered within 4 weeks or 5 half-lives prior to the first dose, whichever is shorter; The use of small molecule targeted therapy (including small molecule tyrosine kinase inhibitors) within 5 days, palliative radiotherapy within 2 weeks (but palliative radiotherapy for bone lesions is allowed), modern traditional Chinese medicine treatment approved by NMPA for anti-tumor treatment, etc. Patients with recurrent NPC suitable for radical local treatment (surgery or radiotherapy) should be excluded. The history of severe cardiovascular and cerebrovascular diseases in the past six months was screened, such as symptomatic congestive heart failure (CHF) ≥ grade 2 (CTCAE v5.0), New York Heart Association (NYHA) ≥ grade 3 heart failure, unstable angina pectoris, acute coronary syndrome, myocardial infarction, cerebrovascular accident, transient ischemic attack, cerebral infarction, etc. Prolonged QT interval (QTc > 450 msec in men or QTc > 470 msec in women; QTc interval calculated with Fridericia's formula), complete left bundle branch block, degree III atrioventricular block, and frequent and uncontrollable arrhythmias: Such as atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter (except transient atrial fibrillation, atrial flutter). Other malignant tumors diagnosed within 3 years before the first dose, except those with radical basal cell carcinoma, squamous cell carcinoma, and/or radical resection carcinoma in situ considered by investigators to be eligible for enrollment. Hypertension poorly controlled by two antihypertensive drugs (systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg). History of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), current ILD, or suspicion of such disease on imaging during screening. Complicated pulmonary diseases leading to clinically severe respiratory impairment, including but not limited to the following: a. Any underlying pulmonary disease (e.g., pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease within 3 months before randomization), b. Restrictive lung disease. Patients with central nervous system (CNS) metastasis and/or carcinomatous meningitis (meningeal metastasis) (intracranial invasion of nasopharyngeal carcinoma was excluded). Patients with a history of allergy to recombinant humanized antibodies or to any of the excipients of BL-B01D1. A history of autologous or allogeneic stem cell transplantation. Human immunodeficiency virus antibody (HIVAb) positive, active hepatitis B virus infection (HBV-DNA > 103 copies/ml) or hepatitis C virus infection (HCV-RNA > the lower detection limit of research center). Severe infection (CTCAE > grade 2), such as severe pneumonia, bacteremia, septicemia, tuberculosis, etc., within 4 weeks before the first dose of study drug; Signs of pulmonary infection or active pulmonary inflammation within 4 weeks before the first dose of study drug. Patients with massive or symptomatic effusions, or poorly controlled effusions (poorly controlled was defined as requiring 2 or more paracentesis and drainage within a month). Received other unmarketed investigational drug or treatment within 4 weeks before the first dose. Have a history of severe neurological or psychiatric disorders, including but not limited to dementia, depression, seizures, bipolar disorder, etc. Severe unhealed wound, ulcer, or fracture within 4 weeks before consent signing. Subjects with clinically significant bleeding or obvious bleeding tendency within 4 weeks before signing the informed consent, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, vasculitis, etc. History of intestinal obstruction, inflammatory bowel disease, or extensive bowel resection or presence of Crohn's disease, ulcerative colitis, or chronic diarrhea. Subjects who are scheduled to receive live vaccine or receive live vaccine within 28 days before the first dose. Other conditions for participation in the trial were not considered appropriate by the investigator.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<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>|
| Experimental: Control group<br>Participants receive capecitabine, gemcitabine, docetaxel in 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: capecitabine<br>* Oral administration<br>Drug: gemcitabine<br>* Administration by intravenous infusion<br>Drug: docetaxel<br>* Administration by intravenous infusion<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the number of CR and PR in the treatment and control groups divided by the number of that group in the full analysis set (FAS). | Up to approximately 24 months | 
| Overall survival (OS) | Overall survival (OS) is defined as the time between the subject's randomization date and subject's death. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Progression-free survival (PFS) as assessed by BIRC was defined as the time between the date subjects were randomized and the first observation of disease progression (based on BICR's image-based assessment) or death. | Up to approximately 24 months | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) : Percentage of all randomized subjects who rated the best overall response (BOR) as complete response (CR), partial response (PR), and disease stabilization (SD) according to RECIST 1.1 criteria. | Up to approximately 24 months | 
| Duration of Response (DOR) | Duration of Response (DOR) : defined as the period from the date when tumor response is first recorded to the date when objective tumor progression is first recorded or the date of death. | Up to approximately 24 months | 
| 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 approximately 24 months | 
| T1/2 | Half-life (T1/2) of BL-B01D1 will be investigated. | Up to approximately 24 months | 
| Anti-drug antibody (ADA) | Frequency of anti-BL-B01D1 antibody (ADA) will be investigated. | Up to approximately 24 months |