A Study of B1962, a PD-L1/VEGF Bispecific Antibody Fusion Protein, for Advanced Solid Tumors

Study Overview
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Brief Summary
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This study is to characterize the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of B1962, a PD-L1/VEGF bispecific antibody fusion protein, as a single agent in adult subjects with advanced solid tumor malignancies. The study consists of two parts: a once-weekly (QW) dosing phase and a biweekly (Q2W) dosing phase, which will explore the possibility of Q2W dosing of B1962 based on the PK data obtained in the QW phase. The study will determine the maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D) for B1962 as a single agent.

Official Title
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A Multicenter, Open-label, Dose-escalating Phase I Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of B1962 Injection in the Treatment of Advanced Malignant Solid Tumors

Conditions
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Neoplasms Malignant

Intervention / Treatment
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* Drug: B1962


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: written and signed informed consent. Age ≥ 18 years and ≤ 75 years at the time of signing the informed consent form. Patients with histologically or cytologically confirmed advanced malignant solid tumors who have failed or failed to respond to standard therapy, or who are intolerant of standard therapy, or who have no standard effective treatment regimen, or who have refused standard therapy (posterior and endline). willing and able to comply with all study procedures. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1. Life expectancy ≥ 3 months. Subjects must have at least one measurable lesion according to RECIST Version 1.1 Adequate organ and bone marrow function Females of childbearing potential and non-sterilized males who are sexually active must use an effective method of contraception from screening until 120 days after final dose of investigational product or women of non child bearing potential. Exclusion Criteria: Patients receiving immune checkpoint inhibitors (ICIs) or VEGF/VEGFR inhibitors within 28 days prior to the first dose of the study drug. Known allergy or reaction to any component of the B1962 formulation or history of severe hypersensitivity reactions to other large protein agents/mAbs or BsAbs. Female patients who are pregnant or breastfeeding. Subjects has received major surgical procedure within 4 weeks prior to the first dose of B1962, or is scheduled to receive major surgical procedure during the current study period Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v5.0 Grade 0 or 1 (except for alopecia). Patients with untreated or clinically symptomatic brain metastases, spinal cord compression, cancerous meningitis, or other evidence that the patient's brain or spinal cord metastases have not been controlled (except in cases where the patient has been treated and has stable symptoms, imaging shows stability for at least 4 weeks prior to the first dose, and there is no evidence of brain edema and no need for glucocorticoid therapies) Patients with clinically symptomatic or recurrent pleural effusions, pericardial effusions or ascites requiring repeated drainage Imaging at the screening period showed that the tumor was wrapped around important blood vessels or had significant necrosis or cavitiation, and the investigators judged that entering the study would cause bleeding risk Known history of HIV infection or acquired immunodeficiency syndrome-related disease Patients with hepatitis B or C infection; or known active syphilis infection. Uncontrolled infections requiring systemic therapy within 4 weeks prior to the first dose of study drug. Subjects with clinically significant cardiovascular disease; uncontrolled hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) or poor compliance with antihypertensive therapy; major vascular disease. History of Coagulation disorders, bleeding disorders, or other conditions judged by the investigator to be a risk of bleeding within 6 months prior to the first dose. pulmonary hemorrhage/hemoptysis ≥ grade 2 (according to NCI-CTCAE v5.0) within 1 month prior to first drug administration biopsy or other minor surgery, excluding placement of vascular access devices, within 7 days prior to the first dose of B1962 History of arterial or venous thrombosis, or stroke or transient ischemic attack within 6 months prior to the first dose of B1962 Current unstable dose of anticoagulant or thrombolytic medication within 14 days of the first dose of B1962. Note: prophylactic use of low molecular heparin is acceptable. Aspirin (> 325 mg/day) or NSAIDs treatment within 14 days of first dose of B1962 Uncontrolled diabetes mellitus (HbA1c >8%) on standard therapy Active or prior documented idiopathic pulmonary fibrosis or idiopathicpneumonia; current acute lung disease, interstitial lung disease or pneumonia (except localized interstitial pneumonia due to radiotherapy induction), pulmonary fibrosis, etc.; severe respiratory distress, pulmonary insufficiency or continuous oxygenation Active or prior documented of autoimmune disease requiring systemic therapy within 2 years prior to screening. Note: Enrollment is permitted in the following conditions: hypothyroidism that can be controlled by hormone replacement therapy alone, skin conditions that do not require systemic therapy (e.g. vitiligo, psoriasis), and controlled celiac disease. Subjects with a condition requiring systemic treatment with either corticosteroid (> 10 mg daily ) or other immunosuppressive medications within 14 days of first study drug administration (topical or physiological hormones dose is acceptable) Receipt of any systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is longer) prior to first dose, small molecule tyrosine kinase-targeted agents therapy or immunomodulatory therapy within 2 weeks prior to first dose; or herbal or proprietary Chinese medicines with antitumor indications within 1 week prior to the first dose. For hepatocellular carcinoma: receipt of local area treatment of the liver within 4 weeks prior to the first dose of B1962 History of organ or hematopoietic stem cell transplantation requiring immunosuppressive medications History of other neoplasms within 5 years prior to screening, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer in situ that has undergone successful radical surgery Received attenuated vaccination within 4 weeks prior to screening or planning to receive attenuated vaccination during the study period Patients who have participated in a clinical study and received study drug within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose History of alcohol or drug abuse within 12 months prior to the first dose. Known history of psychiatric disorder that may affect trial compliance Other serious systemic disease, abnormal laboratory tests, or other reasons deemed inappropriate for subjects 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>B1962 0.035mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 2<br>B1962 0.12mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 3<br>B1962 0.4mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 4<br>B1962 1.2mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 5<br>B1962 4mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 6<br>B1962 8mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 7<br>B1962 11mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 8<br>B1962 15mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 9<br>B1962 20mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|
| Experimental: Cohort 10<br>B1962 25mg Open Lable | Drug: B1962<br>* B1962 is a PD-L1/VEGF bispecific antibody fusion protein.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT Assessment | Toxicity associated with the treatment of the investigational drug B1962 | From Day1 to Day15 after first dose of B1962 | 
| AE Assessment | The frequency of AE | From first dose of B1962 until 28 days after the last dose of B1962. | 
| 12-lead ECG Assessment | Changes of 12-lead ECG from baseline | From first dose of B1962 until 28 days after the last dose of B1962. | 
| Eastern Cooperative Oncology Group score Assessment | Changes of Eastern Cooperative Oncology Group score from baseline | From first dose of B1962 until 28 days after the last dose of B1962. | 
| Determine the maximum tolerated dose (MTD) |  | From first dose of B1962 until 28 days after the last dose of B1962 | 
| Determine the recommended phase II dose (RP2D) |  | From first dose of B1962 until 28 days after the last dose of B1962 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) Analysis |  | From first dose of B1962 through 7 days of deciding to stop research treatment by subjects | 
| Area under the plasma concentration versus time curve (AUC) Analysis |  | From first dose of B1962 through 7 days of deciding to stop research treatment by subjects | 
| Terminal elimination half-life(t1/2) Analysis |  | From first dose of B1962 through 7 days of deciding to stop research treatment by subjects | 
| Time to reach the maximum observed concentration(Tmax) Analysis |  | From first dose of B1962 through 7 days of deciding to stop research treatment by subjects | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) |  | From first dose of B1962 until 28 days after the last dose of B1962 |