A Study to Evaluate YH001 in Subjects With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is an open-label, dose-escalation study of the study drug YH001 . The study is designed to determine the safety, tolerability and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of YH001 in subjects with advanced solid tumors.

Detailed Description
-----------------
This is a single arm clinical trial in subjects with advanced solid tumor receiving multiple doses of YH001 intravenously (IV). YH001 will be administered (IV) in 19-37 patients with advanced solid tumors. An accelerated titration method followed by a traditional 3+3 dose escalation scheme will be utilized to determine MTD(maximum tolerated dose) and/or RP2D(recommended phase 2 dose). Patients will be dosed at Dose A, Dose B, Dose C, Dose D, Dose E, Dose F and Dose G every 3 weeks (Q3W) for 15 weeks (5 cycles).

Official Title
-----------------
A Open-Label, Phase I Dose Escalation Study to Evaluate the Safety, Tolerability,Efficacy and Pharmacokinetics of YH001 in Subjects With Advanced Solid Tumors

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

Intervention / Treatment
-----------------
* Drug: YH001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged ≥ 18 years; Patients with histologically or cytologically confirmed solid tumors who have failed standard of care or have no standard of care; Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1; Have life expectancy of at least 3 months based on investigator's judgement; Organ function levels must meet the following requirements: A:Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 x 10^9/L, hemoglobin (Hb) ≥ 100 g/L ; B:Liver: serum total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (patients with primary liver cancer or liver metastases: AST and/or ALT < 5 × ULN); C:Kidney: creatinine clearance (CrCL) ≥ 50 mL/min; International normalized ratio (INR) ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN, activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN; All women of reproductive potential, men whose partner is a woman of reproductive potential, or their spouses should use adequate barrier contraception throughout the study and for 3 months after the last dose; Voluntary and agree to sign the informed consent and follow the study treatment protocol as well as follow-up plan. Exclusion Criteria: Subjects with prior anti-CTLA-4 checkpoint inhibitors should be excluded; Patients with any other malignancy within the past 5 years or currently, except for completely cured non-melanoma skin cancer, carcinoma in situ of the cervix, and ductal carcinoma in situ of the breast; Received other anti-tumor therapies (such as chemotherapy, radiotherapy, surgery, endocrine therapy, targeted therapy, immunotherapy, etc.) within 4 weeks or 5 half-lives (whichever is longer) before the first dose, or received modern Chinese medicine preparations with anti-tumor effect approved by NMPA within 2 weeks prior to the first dose; Major surgery (excluding vascular access establishment surgery) was received within 4 weeks prior to the first dose; Has received immunosuppressive therapy within 4 weeks prior to the first dose. However, enrollment is permitted under the following circumstances: In the absence of active autoimmune disease, patients are allowed to receive inhaled or topical glucocorticoids, or other glucocorticoids at doses ≤ 10 mg/day prednisone equivalent. Patients with primary central nervous system (CNS) tumors, or symptomatic CNS tumors, or spinal cord compression, or carcinomatous meningitis; with the following exceptions: Patients with asymptomatic brain metastases (i.e., no progressive central nervous system symptoms due to brain metastatic sites, no need for corticosteroids, and lesion size ≤ 1.5 cm); Patients whose symptoms are controlled by treatment, i.e., their condition is stable and asymptomatic at least 4 weeks after treatment; Use of any other study drug within 4 weeks prior to the first dose, or participation in other clinical studies; Have received live or attenuated vaccines within 4 weeks prior to the first dose; Patients with known severe allergic reactions (≥ Grade 3) to the active ingredient and excipients of the investigational drug, other monoclonal antibodies or Immuno-oncology drugs; Toxic and side effects caused by prior anti-tumor therapy before the first dose did not recover to ≤ Grade 1 (CTCAE v5.0), except for alopecia and sensory neuropathy below Grade 2; History of interstitial pneumonia or non-infectious pneumonitis requiring corticosteroids, except for radiation therapy, or current presence of interstitial pneumonia or non-infectious pneumonitis; ≥ Grade 2 immune-related pneumonitis occurred during prior immunotherapy; History of ≥ Grade 3 immune-related adverse reactions or any adverse reactions leading to discontinuation of immunotherapy during prior immunotherapy; Past or existing active tuberculosis ; Patients with active auto-immune disease, history of auto-immune disease requiring systemic therapy, or history of auto-immune disease within 2 years prior to the first dose, with the following exceptions: leucoderma, childhood asthma/specific reactions, type I diabetes mellitus, hypothyroidism which can be treated with replacement therapy; Clinically uncontrollable disease, including, but not limited to, severe diabetes (fasting glucose > 250 mg/dl,1 mg/dl = 18 mmol/L), uncontrollable hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg), or other serious disease requiring systemic treatment; Patients with active infections, including active hepatitis B, active hepatitis C, and human immunodeficiency virus infection; Patients with active infection requiring intravenous infusion; Serious cardiovascular and cerebrovascular diseases, such as cerebrovascular rupture, stroke, myocardial infarction, unstable angina pectoris, congestive heart failure (New York Heart Association Grade ≥ II), severe uncontrolled arrhythmia, etc., occurred within 6 months prior to the first dose; Patients with clinically significant ECG abnormalities: QTcF ≥ 470 msec (corrected by Fridericia), or having history of congenital long QT syndrome, or taking any known QTc prolonging medication; Patients who have received allogeneic bone marrow transplant or organ transplant; Known psychiatric disorders, drug abuse, drug use, or alcohol dependence that may affect trial compliance; Other conditions that were considered not suitable for the study 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention/treatment<br>All subject will receive YH001 intravenously as single agent every three weeks (Q3W) for up to 1 years, until intolerable toxicity, confirmed disease progression, withdrawal of consent, or Investigator decision, whichever comes first. | Drug: YH001<br>* YH001 will be administered intravenously over 60minutes every three weeks (Q3W) for up to 1 years .<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety and tolerability profile of YH001 (adverse events) | The safety profile of YH001 will be assessed by monitoring the adverse events (AE) per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | From screening up to 1 year | 
| Maximum tolerated dose (MTD) | The MTD will be determined based on the data of safety and tolerability | Cycle 1 of each cohort. Duration of one cycle is 21 day | 
| Recommended phase 2 dose (RP2D) | The RP2D will be determined based on the data of safety and tolerability | Cycle 1 of each cohort. Duration of one cycle is 21 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration (Cmax) | To determine the PK profile of YH001 | Up to 1 year | 
| Trough concentration before the next dose is administered (Ctrough) | To determine the PK profile of YH001 | Up to 1 year | 
| Time to reach maximum serum concentration (Tmax) | To determine the PK profile of YH001 | Up to 1 year | 
| Clearance (CL) | To determine the PK profile of YH001 | Up to 1 year |