Phase I Study of KY-0118 in Subjects With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This dose escalation and dose expansion study is to evaluate and characterize the tolerability, safety, pharmacokinetics and efficacy profile of single agent KY-0118 in Locally Advanced or Metastatic Solid Tumor Patients.

Detailed Description
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For Phase Ia It aims to evaluate the safety, tolerability, pharmacokinetic characteristics, pharmacodynamic effect, immunogenicity in subjects with locally advanced or metastatic solid tumor patients , and determine the appropriate dose of KY-0118. For Phase Ib it aims is to further evaluate the efficacy, safety, tolerability, pharmacokinetic properties, pharmacodynamic effects and immunogenicity of KY-0118 with appropriate dose groups (approximately 3-5 dose groups) in different Administration manner.

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KY-0118 in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions
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Neoplasms, Neoplasms by Histologic Type

Intervention / Treatment
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* Drug: KY-0118
* Drug: KY-0118
* Drug: KY-0118


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old and ≤75 years old, male or female; Subjects with a documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; progression or are intolerant to existing standard therapy or subjects without standard therapy; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；Expected survival time≥ 12 weeks; At least one measurable lesion per RECIST 1.1 (without local treatment or progress after local treatment); Adequate organ function; Toxicity from prior anticancer therapy recovered to ≤ grade 1 prior to the first dose of study drugs; Signed informed consent and willingly adherence to the experimental treatment protocol and visit plan. Exclusion Criteria: Specific anti-tumor treatment prior to use of study treatment; Immunosuppressants or systemic hormone therapy were being used and were not discontinued within 2 weeks prior to enrollment; IL-2 treatment within 6 months prior to the first dose of study drugs; Any immune related adverse events (irAE) that have occurred during previous immunotherapy medication, with a grade of ≥ 3 or leading to termination of immunotherapy; Primary Central Nervous System (CNS) Malignant Tumors or Active CNS Metastasis with Local Treatment Failure; Any severe and/or uncontrolled diseases, including but not limited to: uncontrolled hypertension or pulmonary hypertension or unstable angina; Chronic heart failure; Valve disease; Severe arrhythmia; Had myocardial infarction or bypass or stent surgery within 6 months before screening; History of arteriovenous thromboembolism within 6 months prior to screening； Moderate or severe respiratory distress at rest due to advanced malignant tumors or their complications or severe primary lung diseases；or a current need for continuous oxygen therapy, or a current history of interstitial lung disease (ILD) or pneumonia, severe chronic obstructive pulmonary disease, severe pulmonary insufficiency, symptomatic bronchospasm, etc. ; Uncontrolled bleeding or known tendency to bleed; Patients with chronic Crohn's disease and ulcerative colitis;Patients with hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis syndrome;Patients with a history of intestinal perforation and fistula, but not cured after surgical treatment;Esophagogastric varices; Third space effusion that cannot be controlled by puncture and drainage treatment and require repeated drainage or have obvious symptoms; Patients who require extensive fluid replacement assessed by investigators; Active hepatitis B or active hepatitis C; Active infectious process; A history of immunodeficiency; Autoimmune diseases, including but not limited to systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis, autoimmune thyroid disease, multiple sclerosis, etc.; Patients with allergic constitution, or known to have a history of allergy to IL-2 or PD-1/PD-L1 drugs or any of their components, or known to have a history of severe allergic reactions to fusion proteins; History of other malignancies within 5 years prior to screening; Surgery (other than diagnostic biopsy) within 4 weeks prior to screening or planned to have surgery during the study period; Had received live vaccine within 4 weeks before the first dose or planned to receive live vaccine during the trial; History of neurological or psychiatric disorders, such as epilepsy, dementia, altered mental status, and poor compliance; History of alcohol or drug abuse within the last 1 year; Women who are pregnant or breastfeeding. Patients unwilling to use a highly effective method of contraception during the study period and for 6 months after receiving the trial drug; Attended other study within 4 weeks prior to screening; Other conditions deemed unsuitable for inclusion by the investigators.

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: KY-0118<br> | Drug: KY-0118<br>* KY-0118 is to be injected intravenously with a dose of 0.3μg/kg, 1μg/kg, 3μg/kg, 6μg/kg, 12μg/kg, 24μg/kg, 36μg/kg, 48μg/kg or 64μg/kg until disease progresses or unacceptable tolerability occurs;<br>|
| Experimental: Cohort1: KY-0118<br> | Drug: KY-0118<br>* KY-0118 is to be injected intravenously with a dose of dose1 dose5 weekly until disease progresses or unacceptable tolerability occurs;<br>|
| Experimental: Cohort2: KY-0118<br> | Drug: KY-0118<br>* KY-0118 is to be injected subcutaneously with a dose of dose1 dose5 weekly until disease progresses or unacceptable tolerability occurs;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with dose-limiting toxicity (DLT) |  | 21 days during the first 3-week cycle | 
| Adverse Event | Incidence of untoward medical occurrences (adverse event = AE) in a participant who received study drug. Adverse events will be evaluated by dosing cohort and recorded according to NCI CTCAE Version 5.0. | Up to 28 days post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Peak expansion | Up to 7 days post last dose | 
| Ctrough | Trough concentration | Up to 7 days post last dose | 
| Tmax | time to peak expansion | Up to 7 days post last dose | 
| T1/2 | Elimination half-life | Up to 7 days post last dose | 
| AUC | Area under curve | Up to 7 days post last dose | 
| CL | Clearance rate | Up to 7 days post last dose | 
| Regulatory t cells（Tregs） | Levels of Tregs in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| CD4+ T lymphocyte count | Levels of CD8+ T lymphocyte count in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| CD8+ T lymphocyte count | Levels of CD8+ T lymphocyte count in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| NK cells count | Levels of NK cells count in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| IL-6 | Levels of IL-6 in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| IFN-γ | Levels of IFN-γ in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| TNF-ɑ | Levels of TNF-ɑ in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| Granzyme B | Levels of Granzyme B in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| Perforin | Levels of perforin in peripheral blood at baseline and during administration; | Up to 7 days post last dose | 
| Objective response rate (ORR) | To evaluate the preliminary antitumor activity of KY-0118 | Up to 28 days post last dose | 
| Progression-free survival (PFS) | To evaluate the preliminary antitumor activity of KY-0118 | Up to 28 days post last dose | 
| Duration of response(DOR) | To evaluate the preliminary antitumor activity of KY-0118 | Up to 28 days post last dose | 
| Disease control rate (DCR) | To evaluate the preliminary antitumor activity of KY-0118 | Up to 28 days post last dose | 
| The incidence of ADA of KY-0118 | Each subject will be tested for anti-drug (KY-0118) antibody (ADA) | Up to 7 days post last dose | 
| The incidence of NAb of KY-0118 | Each subject with ADA-positive serum samples will continue to be tested for neutralizing antibodies (NAb) | Up to 7 days post last dose | 
| PD-1 receptor occupancy rate |  | Up to 7 days post last dose | 
| IL-2 receptor occupancy rate | IL-2 receptor occupancy of Nk cells, CD8+ T lymphocyte and CD4+T lymphocyte | Up to 7 days post last dose | 
| Ki67 phenotype | Ki67 phenotype of Nk cells and CD8+T lymphocyte | Up to 7 days post last dose |