A Study of ZL-1211 in Patients With Advanced Solid Tumor

Study Overview
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Brief Summary
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This study is a Phase I/II, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of ZL-1211 administered by IV infusion on a every 2 weeks (Q2W) schedule.

Detailed Description
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The study consists of two stages, Phase I -Dose Escalation Phase to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of ZL-1211, and Phase II -Cohort Expansion Phase to further define the safety and initial antitumor activity of ZL-1211 with the dose established in the Dose Escalation Phase.

Official Title
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A Phase I/II, First-in-Human, Open-Label, Dose Escalation Study of ZL- 1211 in Patients With Unresectable or Metastatic Solid Tumor

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: ZL-1211


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible to be included in the study only if all the following inclusion criteria apply: Adults≥ 18 years of age. Willing and able to provide signed and dated informed consent prior to any study related procedures and willing and able to comply with all study procedures. All patients from Phase I and Phase II are required to provide tumor tissue for CLDN18.2 IHC assessment, and only patients with CLDN18.2-positive tumors will be included in this study. Patients with histologically or cytologically confirmed metastatic or locally advanced solid tumors, refractory to standard treatment Evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Adequate hepatic function Total bilirubin ≤ 1.5 × upper limit of normal (ULN). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; AST or ALT ≤ 5 × ULN if liver metastases are present. Adequate renal function, as defined by serum creatinine < 1.5 × ULN OR calculated creatinine CL > 40 mL/min, Cockroft-Gault Equation: Hematological function defined as: Absolute neutrophil count ≥ 1.5 × 109/L without growth factor support in the 2 weeks prior to screening. Platelet count ≥ 100 × 109/L without transfusion in the 2 weeks prior to screening. Hemoglobin ≥ 9 g/dL without transfusion in the 2 weeks prior to screening. Prothrombin time, international normalized ratio or/and activated partial thromboplastin time < 1.5 × ULN. Recovery, to Grade 0-1, from AEs related to prior anticancer therapy except alopecia, < Grade 2 sensory neuropathy, lymphopenia. Exclusion Criteria: Patient with known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome related illness or known active or chronic hepatitis B virus infection or hepatitis C virus. Any uncontrolled active infection. Previous exposure to any CLDN18.2 antibody or CLDN18.2 chimeric antigen receptor T cell therapy. Newly diagnosed or symptomatic brain metastases anticonvulsants are allowed. Severe cardiovascular disease; New York Heart Association Class II-IV heart failure within 6 months of screening; uncontrolled arrhythmia within 6 months of screening. Anticancer therapy or radiation therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to screening; palliative radiotherapy within 2 weeks prior to screening. Major surgery within 4 weeks prior to first dose; minor surgery within 2 weeks prior to first dose. Symptomatic intrinsic lung disease (chronic obstructive pulmonary disease, pulmonary fibrosis). Gastrointestinal abnormalities including: Documented unresolved gastric outlet obstruction or persistent vomiting defined as ≥ 3 episodes within 24 hours. Active peptic ulcer disease required treatment in the past 3 months. Gastrointestinal bleeding as evidenced by hematemesis, hematochezia, or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy. Documented active colitis within 4 weeks prior to study entry, including infectious colitis, radiation colitis and ischemic colitis. History of ulcerative colitis or Crohn's disease. Patient has received systemic immunosuppressive therapy, including systemic corticosteroids 2 weeks prior to first dose of study drug.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I, the Dose Escalation Phase of the study will enroll patients with locally advanced or metastatic solid tumors of any histology with positive CLDN18.2. Phase II, the Cohort Expansion Phase of the study, will be conducted after determination of the dose level (RP2D) for cohort expansion based on the results of Phase I to explore the preliminary efficacy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZL-1211 monotherapy<br> | Drug: ZL-1211<br>* Phase 1 dose escalation part will enroll about 12-42 patients, Phase 2 dose expansion part will enroll about 15-40 patients in each cohort<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I ：MTD or MAD | To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of ZL-1211 | One month | 
| Phase I and Phase II: safety and tolerability | Incidence of Treatment-Related Adverse Events as Assessed by CTCAE v5.0 | Approximately 10 months | 
| Phase II: preliminary antitumor activity | Objective response rate defined as the proportion of patients with partial response (PR) proportion of patients with partial response (PR) or complete response (CR) based on Investigator assessment of tumor lesions per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Approximately 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I and Phase II: pharmacokinetics (PK):AUC | Area under the curve (AUC) | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):Cmax | Maximum serum concentration (Cmax) | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):Tmax | Time to reach Cmax (Tmax) | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):Ctrough | Ctrough | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):Vss | Volume of distribution at steady state (Vss) | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):CL | Clearance (CL) | Approximately 10 months | 
| Phase I and Phase II: pharmacokinetics (PK):t1/2 | Half-life (t1/2) | Approximately 10 months | 
| Phase I and Phase II: immunogenicity | Incidence of anti-drug antibodies (ADAs) | Approximately 10 months | 
| Phase I and Phase II: immunogenicity | Quantity of anti-drug antibodies (ADAs) | Approximately 10 months | 
| Phase II: preliminary antitumor activity | Duration of response (DOR), defined as the time from the first date of objective response (CR or PR) to the first documented date of disease progression per RECIST v1.1 or the date of death due to any cause, whichever occurs first | Approximately 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLDN18.2, Solid tumor