Phase I Study of KN035 in Chinese Subjects With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This dose escalation and dose expansion study is to evaluate and characterize the tolerability and safety profile of single agent KN035 in Chinese adult subjects with unresectable advanced carcinoma.

Detailed Description
-----------------
Dose escalation study is to evaluate the safety and tolerability of KN035 in advanced and metastatic solid tumor. Six dose levels are planned and include: 0.1, 0.3, 1.0, 2.5, 5, 10 mg/kg/dose. Subjects will be assigned to a dose level in the order of study entry. The first cohort of 1 subject will receive KN035 at 0.1 mg/kg/dose as a subcutaneous (sc) injection every week for a total of 4 injections (Days 1, 8, 15 and 22) in the first 28-day cycle. For the first 2 cohorts (0.1 and 0.3 mg/kg/dose), only one subject will be enrolled in each cohort until 1 subject experiences a ≥ Grade 2 drug-related adverse event in the first cycle, then 2 additional subjects will be enrolled at this cohort. Thereafter, the study will become the traditional 3+3 design with 3 or 6 subjects treated at this dose level and all subsequent dose levels depending upon the incidence of DLTs. However, if no ≥ Grade 2 drug-related adverse event occurs in the first 2 cohorts, starting with cohort 3, the study will become the traditional 3+3 design with 3 or 6 subjects enrolled. Dose expansion-1 study is planned to conduct in advanced hepatocellular cancer subjects at 2.5 mg/kg and 5 mg/kg dose level, respectively. Dose expansion-2 study is planned to conduct in advanced solid tumor subjects at 2.5 mg/kg and 5 mg/kg dose level, respectively

Official Title
-----------------
A Phase I, Single Arm, Multiple Dose, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KN035 Administered in Subcutaneous Injection as a Single Agent to Subjects With Advanced Solid Tumors

Conditions
-----------------
Solid Tumors

Intervention / Treatment
-----------------
* Drug: KN035


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria for dose escalation study: Subject is male or female ≥ 18 years and ≤ 70 years of age on the day of signing informed consent,and subject has voluntarily agreed to participate by giving written informed consent. Subjects must have a histopathological diagnosis of any locally advanced or metastatic solid tumor, Subjects must have failed established standard medical anti-cancer therapies ( have disease progression after the therapies or be intolerant to the therapies) or Subjects refuse to standard therapies, or no effective treatment. Measurable disease as defined by RECIST v1.1. Subject must have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Life expectancy ≥ 12 weeks. Subject must have adequate hematologic and organ function. Female subject of childbearing potential has a negative serum pregnancy test. Female subjects of childbearing potential and male subjects with partner of childbearing potential should agree to keep abstinence (refuse to heterosexual intercourse) or use one or more methods of contraception of which the failure rate is less than 1% per year starting with the first dose of study drug through at least 6 months after the last dose of study therapy. Main Inclusion Criteria for dose expansion study: Histologic confirmation of advanced hepatocellular carcinoma, disease not eligible for curative surgical and/or locoregional therapies, OR progressive disease after surgical and /or locoregional therapies. At least one RECIST 1.1 measurable untreated lesion. All subjects must have at least one previously untreated, unidimensionally measurable lesion by contrast-enhanced spiral computed tomography (CT) ≥10 mm or contrast enhanced dynamic magnetic resonance imaging (MRI) scan ≥10 mm (malignant lymph nodes must be ≥15 mm on short axis). Subject is male or female ≥ 18 years and ≤ 75 years of age on the day of signing informed consent,and subject has voluntarily agreed to participate by giving written informed consent. Subject must have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Cirrhotic status of Child-Pugh Class A. Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or HCV-HCC defined as follows: i) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV DNA < 104 copies/ml and must be on antiviral therapy. ii) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA or antibody. Life expectancy ≥ 12 weeks. Subject must have adequate hematologic and organ function. Main Exclusion Criteria: Subject Is currently participating and receiving study therapy or has participated in a study of an investigational agent and receive study therapy within 28 days of the first dose of study drug. Subject has not recovered to CTCAE Grade 1 or better from the adverse events due to cancer therapeutics administered Subject has a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds (ms)), or a history of additional risk factors for torsade de pointes (TdP, e.g., heart failure, hypokalemia, family history of Long QT Syndrome), or is using concomitant medications that prolong the QT/QTc interval. Subject has had antineoplastic therapy within 4 weeks prior to the first dose of study therapy KN035. Subject is, with one year of the time signing informed consent, a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). Subjects with symptomatic ascites, pleural effusion or pericardial effusion. Subject is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study. Subject has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and are off steroids for at least 7 days from first dose of KN035. Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Subject has Leptomeningeal disease. Subject previously had a severe hypersensitivity reaction to treatment with another mAb. Subject has an active infection (CTCAE≥Grade 2) with 4 weeks of the first dose. Subject is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active hepatitis B (HBV surface antigen positive and HBV DNA ≥ 104 copies/ml)or hepatitis C or tuberculosis (HCV antibody positive and HCV-RNA≥ 103 copies/ml). Subject has received or will receive a live vaccine within 4 weeks prior to the first administration of study drug. Addtional exclusion criteria for dose expansion study: Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. The patient accepted any anti-cancer therapy within 28 days prior to the first dose of study drug including surgery, radiotherapy, biotherapy, immunotherapy and/or locoregional therapy (eg: radiofrequency ablation [RFA], percutaneous ethanol [PEI] or acetic acid injection [PAI], cryoablation, high-intensity focused ultrasound [HIFU], transarterial chemoembolization [TACE], transarterial embolization [TAE], etc.) Prior liver transplant or history of hepatic encephalopathy

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: KN035<br>KN035 is to be injected subcutaneously 0.1mg/kg or 0.3mg/kg or 1mg/kg or 2.5mg/kg or 5mg/kg or 10mg/kg weekly until disease progresses or unacceptable tolerability occurs. | Drug: KN035<br>* KN035 is a monoclonal antibody drug which is formulated for subcutaneous injection in a single-use vial (brown neutral borosilicate) containing a total of 300 mg antibody in 1.5 ml of solution.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) in dose escalation study |  | From screening to up to cycle 1 (28 days) | 
| Percentage of participants with adverse events (AEs), serious adverse events and AEs of special interest |  | From screening to up to 1 months after the last dose of study drug (up to approximately 2 years) | 
| ORR of HCC patients in dose expansion study |  | Up to 2 approximately years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Peak Time (Tmax) of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Area under the plasma concentration versus time curve (AUC) of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| t1/2 of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Trough concentration of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Plasma clearance (CL) of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Apparent volume of distribution of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Accumulation rate of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Anti-Drug Antibody of KN035 in Chinese patients |  | From Pre-dose of the first dose to up to cycle 12 | 
| Changes of lymphocyte Subtyping |  | From Pre-dose of the first dose to up to cycle 12 | 
| Changes of cytokine |  | From Pre-dose of the first dose to up to 6 months | 
| Objective Response Rate (ORR) |  | Up to 2 approximately years | 
| Disease Control Rate (DCR) |  | Up to 2 approximately years | 
| Progression-Free survival (PFS) |  | Up to 2 approximately years | 
| Duration of Response (DOR) |  | Up to 2 approximately years | 
| Correlation of tumor response with the PD-L1 expression |  | Up to 2 approximately years | 
| Correlation of the tumor response with the expression of specific gene mutation |  | Up to 2 approximately years | 
| overall survival |  | Up to 2 approximately years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
KN035, phase 1