A Study of HG381 Administered to Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase I, first in human, open-label, non-randomized, multicenter study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy and establish a recommended dose of HG381 administered intravenously (IV) alone in subjects with advanced solid tumors.

Detailed Description
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The trial consists of a dose escalation phase and a cohort expansion phase.In dose escalation phase, escalating doses of HG381 will be evaluated as guided by the traditional 3+3 design . In cohort expansion phase, subjects will receive HG381 alone at a single dose level determined based on the data form dose escalation phase. In total, approximately 57 subjects will participate in the study, approximately 42 in the dose-escalation cohort, and approximately 15 in the expansion cohort.

Official Title
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Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of HG381 as Monotherapy in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: HG381


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent. Life expectancy of at least 3 months. Histological or cytological documentation of an advanced solid tumor，subjects with advanced/recurrent solid tumors, who have progressed on, be intolerant of, or ineligible for, all available therapies for which clinical benefit has been established. Measurable disease per RECIST version 1.1, there is at least one measurable lesion during the screening period. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Adequate organ function : Hematologic system: Hemoglobin ≥9 g/dL, Absolute neutrophil count [ANC] ≥1.5x10^9/L, Platelets ≥100x10^9/L, INR ≤ 1.5 and APTT ≤1.5 x ULN; Hepatic system: Total bilirubin ≤1.5 x ULN, ALT and AST ≤ 2.5 x ULN; Renal system: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min (calculated by the Cockcroft-Gault formula); Cardiac system: left ventricular ejection fraction (LVEF) ≥50% ; QT interval (QTcF) ≤470 ms for women, and ≤450 ms for men; Endocrine system: Thyroid-stimulating hormone (TSH) is within the normal limits. Subjects with fertility must agree to take medically approved effective contraceptive measures during the entire trial period and at least 3 months after the last medication. Exclusion Criteria: Chemotherapy, radiotherapy, biological therapy, endocrine therapy, immunotherapy and other anticancer therapy within 4 weeks. Concurrent medical condition requiring the use of other systemic immunosuppressive treatment within 4 weeks before the first dose of study treatment. Receipt of any live vaccine within 4 weeks of the start of study treatment. Receipt of unmarketed clinical trial drugs or treatments within 4 weeks of the start of study treatment. Receipt of surgery or interventional treatment (excluding tumor biopsy, puncture, etc.) within 4 weeks of the start of study treatment. History or evidence of cardiovascular and cerebrovascular diseases risk. Subjects with uncontrolled diabetes. Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases that have required steroids within 2 weeks prior to first dose of study treatment. Currently or in the past suffering from malignant tumors. Uncontrollable pleural effusion, pericardial effusion or ascites still need to be drained frequently after appropriate intervention. Active or suspected autoimmune disease. History of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis. Toxicity from previous treatment including: Toxicity Grade ≥3 related to prior immunotherapy and that led to study treatment discontinuation; Toxicity related to prior treatment that has not resolved to Grade ≤ 1. Subjects who have acute bacterial, viral or fungal infections and require systemic anti-infective treatment. Positive test for syphilis antibodies or human immunodeficiency virus (HIV) antibodies. Subjects who are allergic to test drugs and excipients. Women who are pregnant or breastfeeding. Known drug or alcohol abuse. Patients with mental or neurological diseases. Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation. Subjects who have a history of serious systemic disease or any other reason are not suitable to participate in this trial as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 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: Part A: HG381 Monotherapy Dose Escalation Cohort<br>Subjects will receive HG381 IV at every one week intervals (Q1W). Escalating doses of HG381 will be evaluated by the traditional 3+3 design. | Drug: HG381<br>* HG381 is available as white to off-white cake or powder for solution for injection at a unit dose strength of 5 mg per vial. HG381 will be administered as IV injection.<br>* Other names: HG381 for Injection;|
| Experimental: Part B: HG381 Monotherapy Dose Expansion Cohort<br>Subjects will be administered the recommended Phase 2 dose of HG381 IV Q1W established in Part A of the study. | Drug: HG381<br>* HG381 is available as white to off-white cake or powder for solution for injection at a unit dose strength of 5 mg per vial. HG381 will be administered as IV injection.<br>* Other names: HG381 for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects achieving Dose-limiting toxicity (DLT) | DLT is defined as an adverse event (AE) that meets protocol defined DLT criteria during cycle 1 and is at least possibly related to study drug. | Up to Day 21 | 
| Maximum Tolerated Dose (MTD) | The maximum tolerated dose (MTD) is defined as the maximum dose where the number of cases of DLT ≤ 1/6 of the total number of cases during the DLT observation period. At least 6 evaluable subjects are required to determine MTD. | Up to 12 months | 
| Number of subjects with adverse events (AEs) and serious adverse events (SAEs) | An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or requires medical judgement. | Up to 24 months | 
| Severity of AEs | The severity of AEs will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) of HG381 | Up to 42 patients with advanced/metastatic solid tumors will be enrolled in Dose Escalation to determine the RP2D of HG381 as monotherapy. | Up to 12 months | 
| Best objective response based on RECIST 1.1 | Best objective response rate is defined as the percentage of subjects with a best overall confirmed CR or PR at any time as per disease-specific criteria. | Up to 24 months | 
| HG381 concentrations in plasma following administration of HG381 alone | Blood samples will be collected at indicated time points for plasma pharmacokinetic (PK) analysis of HG381. | Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days) | 
| Maximum observed concentration (Cmax) following administration of HG381 alone | Blood samples will be collected at indicated time points for plasma PK analysis following administration of HG381 monotherapy. | Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days) | 
| Area under the concentration-time curve (AUC) following administration of HG381 alone | Blood samples will be collected at indicated time points for plasma PK analysis following administration of HG381 monotherapy. | Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days) | 
| Apparent terminal phase half-life (t½) following administration of HG381 alone | Blood samples will be collected at indicated time points for plasma PK analysis following administration of HG381 monotherapy. | Cycle 1 Days 1, Cycle 2 Days 1 and Cycle 3 Days 1: pre-infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days) |