A Study of RC118 Plus Toripalimab in Patients With Locally Advanced Unresectable or Metastatic Solid Tumors

Study Overview
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Brief Summary
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In Phase I, This study will explore the tolerability and safety of RC118 in combination with toripalimab for treatment of patients with locally advanced unresectable or metastatic malignant solid tumors with positive Claudin 18.2 expression, and determine the maximum tolerated dose (MTD) and the recommended dose in phase II clinical trials (RP2D); In Phase IIa, to explore the clinical effectiveness and safety of long-term use of RC118 in combination with toripalimab at RP2D doses for patients with different tumor types.

Detailed Description
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this study is an open, single arm, multi-center Phase I /IIa clinical study. In the phase I, patients with locally advanced unresectable or metastatic malignant solid tumors (gastric cancer, esophageal cancer, gastroesophageal junction cancer, pancreatic cancer, ovarian cancer, cholangiocarcinoma, etc.) that are positive for Claudin 18.2(positive membrane staining observed in any tumor cells) will be included. in Phase I dose escalation phase, 4 dose groups of RC118 will be preset：1.0 mg/kg、1.5 mg/kg、2.0 mg/kg and 2.5 mg/kg, and toripalimab is fixed dose of 3.0mg/mg; In phase IIa cohort expansion phase, with reference to the results of the phase I study, subjects were grouped according to different tumor types, there are at least 20 subjects in each group, initially considering the inclusion of Claudin 18.2 positive (a clear cut-off value will be defined based on the results of Phase I) locally advanced unresectable or metastatic gastric cancer/gastroesophageal junction cancer, and other solid tumors (The specific tumor types and groups will be further adjusted based on the results of the phase I study).

Official Title
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An Open, Multi-center Phase I/IIa Clinical Study of RC118 in Combination With Toripalimab for Treatment of Patients With Locally Advanced Unresectable or Metastatic Malignant Solid Tumors With Positive Expression of Claudin 18.2

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: RC118
* Drug: Toripalimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer to participate in this study and sign written informed consent 18 years old ≤ age ≤ 75 years old, no gender limit ECOG physical status score is 0 or 1 point The expected survival time exceeds 12 weeks In dose escalation part, Inclusion locally advanced or metastatic malignant solid cancer who have previously received at least first-line standard treatment In dose expansion part, inclusion locally advanced or metastatic gastric cancer who have previously received first-line standard treatment; And other locally advanced or metastatic malignant solid cancer who have previously received at least first-line standard treatment The subject agrees to provide freshly collected tumor tissue specimens or collected and preserved tumor tissue specimens within 2 years during the screening period for CLDN 18.2 testing, and must meet the following criteria： A. Phase I dose escalation stage/dose confirmation stage: patients with gastric cancer, esophageal cancer, gastroesophageal junction cancer, pancreatic cancer, ovarian cancer, and cholangiocarcinoma with positive Claudin 18.2 expression (membrane staining is observed in any tumor cells); B. Phase IIa study stage: Patients with gastric cancer, esophageal cancer, gastroesophageal junction cancer, pancreatic cancer, etc. with positive Claudin 18.2 expression (the cut-off value will be clearly defined based on the phase I results) According to the RECIST v1.1 standard, based on imaging examination (CT/MRI), there is at least one measurable or evaluable target lesion Sufficient bone marrow, liver, and kidney functions (subject to the normal value of the clinical trial center): absolute neutrophil count (ANC) ≥ 1.5×109/L, platelet ≥ 100×109/L, hemoglobin ≥ 90 g/ L, serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN), ALT, AST or ALP ≤ 3 times ULN without liver metastasis; ALT, AST or ALP ≤ 5 times ULN with liver metastasis, serum creatinine ≤ 1.5 Times ULN, International Normalized Ratio (INR) ≤ 1.5 times ULN, APTT ≤ 1.5 times ULN Male or female subjects with fertility must agree to take effective contraceptive measures during the study period and within 6 months after the end of the last medication, such as double-barrier contraceptive methods, condoms, oral or injectable contraceptives, intrauterine Exclusion Criteria: Women who are pregnant or breastfeeding, or women whose blood pregnancy test results are positive during the screening period (female subjects who are infertile do not need to undergo a pregnancy test, such as hysterectomy and/or bilateral ovaries in the past Women with resection or amenorrhea ≥12 months) Subjects with positive test results for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), and human immunodeficiency virus antibody (HIV-Ab) during the screening period Subjects who have a history of other acquired or congenital immunodeficiency diseases or organ transplantation Those who have previously received targeted therapy drugs for Claudin 18.2; or participated in clinical trials of other drugs within 4 weeks before the first administration and received trial drugs Have vaccinated within 4 weeks before the first dose or plan to vaccinate any vaccine during the study period People with allergies, or allergic to known research drug ingredients or excipients Combined use of vitamin K antagonist anticoagulant drugs; combined use of therapeutic doses of heparin (subjects using preventive doses of heparin can be included in the study) Received anti-tumor therapy (surgery, chemotherapy, radiotherapy, biological therapy) within 4 weeks before the first administration, and received palliative radiotherapy for bone metastases within 2 weeks The toxicity of previous anti-tumor treatments has not returned to the level 0 or 1 of NCI-CTCAE v5.0 (except for hair loss) There are clinical symptoms of the third space effusion (large amounts of pleural fluid or ascites) that cannot be controlled by drainage or other methods According to the judgment of the investigator, an active infection with clinical significance Combined with other diseases that seriously endanger the safety of the subject or affect the completion of the test, such as gastrointestinal bleeding (within 4 weeks before the first dose), peptic ulcer, intestinal obstruction, intestinal paralysis, interstitial pneumonia, lung Fibrosis, kidney failure, and uncontrolled diabetes QTc interval during the screening period>480 ms (based on the average of 3 screening electrocardiograms); previous family or personal history of long/short QT interval syndrome; ventricular arrhythmia deemed clinically significant by the investigator Medical history, or currently receiving antiarrhythmic drug treatment, or implantation of arrhythmia defibrillation device Past myocardial infarction (within 6 months before the first administration), severe or unstable angina, coronary or peripheral artery bypass grafting, New York Heart Association (NYHA) grade 3 4 heart failure, no Controlled hypertension People who have had alcohol dependence or drug abuse in the past Those who have received systemic steroid therapy for a long period of time (Note: Short-term use (≤ 7 days) and withdrawal> 2 weeks can be selected) Patients who have previously or currently suffered from uncontrolled primary or metastatic brain tumors, and the investigator believes that patients who have been stabilized or whose local treatment has ended may be considered for inclusion in the group Past or current peripheral neuropathy ≥ Grade 2 Past or current mental illness that is difficult to control Past or current mental illness that is difficult to control Other subjects deemed unsuitable to participate in clinical research by the investigator

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: Part A-Arm 1<br>Part A will follow the standard 3+3 dose escalation design, 3 6 participants will be allocated to the first dose group of RC118, and receive a treatment of RC118-ADC (1.0mg/kg) and Toripalimab (3.0mg/kg) followed by 14 days of dose limited toxicity (DLT) observation period. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|
| Experimental: Part A-Arm 2<br>Part A will follow the standard 3+3 dose escalation design, 3 6 participants will be allocated to the second dose group of RC118, and receive a treatment of RC118-ADC (1.5mg/kg) and Toripalimab (3.0mg/kg) followed by 14 days of dose limited toxicity (DLT) observation period. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|
| Experimental: Part A-Arm 3<br>Part A will follow the standard 3+3 dose escalation design, 3 6 participants will be allocated to the Thrid dose group of RC118, and receive a treatment of RC118-ADC (2.0mg/kg) and Toripalimab (3.0mg/kg) followed by 14 days of dose limited toxicity (DLT) observation period. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|
| Experimental: Part A-Arm 4<br>Part A will follow the standard 3+3 dose escalation design, 3 6 participants will be allocated to the last dose group of RC118, and receive a treatment of RC118-ADC (2.5mg/kg) and Toripalimab (3.0mg/kg) followed by 14 days of dose limited toxicity (DLT) observation period. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|
| Experimental: Part B-Arm 1<br>Part B-Arm 1 will include approximately 20 patients with gastric cancer (including gastric esophageal junction). This subject group will receive RC118-ADC and Toripalimab (3.0mg/kg) Day 1 of every 14-day cycle. The starting dose of RC118-ADC for expansion will be derived from the RP2D determined during Part A. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|
| Experimental: Part B-Arm 2<br>Part B-Arm 1 will include approximately 20 patients with pancreatic cancer and other solid tumors. This subject group will receive RC118-ADC and Toripalimab (3.0mg/kg) Day 1 of every 14-day cycle. The starting dose of RC118-ADC for expansion will be derived from the RP2D determined during Part A. | Drug: RC118<br>* RC118 for injection is a novel antibody-drug conjugate, with a Claudin 18.2-targeting antibody and a microtube inhibitor<br>* Other names: RC118 for injection;Drug: Toripalimab<br>* Toripalimab is a recombinant humanized anti-PD1 monoclonal antibody<br>* Other names: JS001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | In the DLT evaluation window (observation period 1-28 days after the first administration), according to the NCI-CTCAE v5.0 grading standard, the investigator or the sponsor believes that toxic reaction which are reasonably related to RC118 + Toripalimab treatment | 28 days after first treatment | 
| The incidence and severity of adverse events (AE) | The incidence and severity of adverse events (AE) | From the day of ICF sign to 90 days after the day of the last treatment | 
| Objective response rate (ORR) | Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | Disease Control Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) or stable disease(SD) | 15 months | 
| Progression-free survival (PFS) | Progression-free Survival (PFS) (median) was determined using the number of months measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression) of participants. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | 15 months | 
| Duration of Remission (DOR) | Duration of response is the length of time that a tumor continues to respond to treatment without the cancer growing or spreading | 15 months | 
| Overall survival (OS) | Overall survival (OS) (median) was determined using the number of months measured from the initial date of treatment to the date of death. | 15 months | 
| RC118 pharmacokinetics: Area under the concentration time curve over the dosing interval. | RC118 pharmacokinetics: Area under the concentration time curve over the dosing interval. | 15 months | 
| RC118 pharmacokinetics: Maximum concentration of the drug (Cmax). | RC118 pharmacokinetics: Maximum concentration of the drug (Cmax). | 15 months | 
| RC118 pharmacokinetics: Time to maximum concentration (Tmax). | RC118 pharmacokinetics: Time to maximum concentration (Tmax). | 15 months | 
| RC118 pharmacokinetics: Elimination half-life (t1/2). | RC118 pharmacokinetics: Elimination half-life (t1/2). | 15 months | 
| RC118 pharmacokinetics: Clearance (CL). | RC118 pharmacokinetics: Clearance (CL). | 15 months | 
| RC118 pharmacokinetics: Mean residence time (MRT). | RC118 pharmacokinetics: Mean residence time (MRT). | 15 months | 
| RC118 pharmacokinetics: Apparent volume of distribution (Vd). | RC118 pharmacokinetics: Apparent volume of distribution (Vd). | 15 months | 
| RC118 pharmacokinetics: Elimination rate constant (λz). | RC118 pharmacokinetics: Elimination rate constant (λz). | 15 months | 
| RC118 immunogenicity: Number of participants with anti-drug-antibody (ADA) | RC118 immunogenicity: Number of participants with anti-drug-antibody (ADA) | 15 months |