A Study of RC108-ADC in Subjects With Advanced Malignant Solid Tumors

Study Overview
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Brief Summary
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This study will evaluate the safety, pharmacokinetics, and effect of RC108-ADC for injeciton in subjects with c-Met positive advanced malignant solid tumors.

Official Title
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A Phase I Study to Evaluate the Safety, Pharmacokinetics, and Effect of RC108-ADC For Injection in Subjects With c-Met Positive Advanced Malignant Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: RC108


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary agreement to provide written informed consent. Male or female, aged between 18 to 70 years. Predicted survival for ≥ 12 weeks. Diagnosed with histologically or cytologically confirmed locally advanced or metastatic solid tumors. Measurable lesion according to RECIST 1.1. c-Met positive as confirmed by the central laboratory. The subject is able to provide specimens from primary or metastatic lesions for c-Met tests. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Adequate organ function, evidenced by the following laboratory results within 7 days prior to the study treatment: Cardiac ejection fraction ≥ 50%. Median QTc < 450 ms. Hemoglobin ≥ 9g/dL; Absolute neutrophil count ≥ 1.5×10^9 /L Platelets ≥ 100×10^9 /L; Total bilirubin ≤ 1.5× ULN; AST and ALT ≤ 2.5×ULN and ≤ 5 x ULN with hepatic metastasis; Serum creatinine ≤1.5×ULN. All female subjects will be considered to be of child-bearing potential unless they are postmenopausal, or have been sterilized surgically. Female subjects of child-bearing potential must agree to use two forms of highly effective contraception. Male subjects and their female partner who are of child-bearing potential must agree to use two forms of highly effective contraception. Willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol. Exclusion Criteria: Known hypersensitivity to the components of RC108-ADC. Toxicity of previous anti-tumor treatment not recovered to CTCAE (v5.0) Grade 0-1 (with exception of Grade 2 alopecia). Uncontrolled pericardial effusion or cardiac tamponade, or pleural or abdominal effusion with clinical symptoms. History of receiving any anti-cancer drug/biologic treatment within 4 weeks prior to trial treatment. History of major surgery within 4 weeks of planned start of trial treatment. Has received a live virus vaccine within 4 weeks of planned start of trial treatment. Currently known active infection with HIV or tuberculosis. Diagnosed with HBsAg, HBcAb positive and HBV DNA copy positive, or HCVAb positive. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or cancers with a similar curative outcome as those mentioned above. Known central nervous system metastases. Uncontrolled hypertension, diabetes, pulmonary fibrosis, acute lung disease, Interstitial lung disease, or liver cirrhosis; Pregnancy or lactation. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RC108<br>Participants will be allocated to one of the following dose groups: 0.1, 0.3, 0.9, 1.5, 2.0, 2.5, and 3.0mg/kg, and receive a treatment of RC108-ADC followed by 21 days of dose limited toxicity (DLT) observation period. | Drug: RC108<br>* RC108 for injection is a novel antibody-drug conjugate, with a c-Met-targeting antibody and a microtube inhibitor.<br>* Other names: RC108 for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Adverse events was assessed by investigator(s) according to NCI-CTCAE v4.03 | From the day of ICF signment to 28 days after the day of the last treatment | 
| Maximum Tolerated dose of RC108 | The dose level in which >= 2 out of 6 patients have dose-limiting toxicity (DLT). The MTD is defined as the previous dose level. | 21 days after first treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) | 24 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. | 24 months | 
| Pharmacokinetics (PK) parameter for total antibody (TAb): Maximum concentration (Cmax) | Cmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for TAb: Time to maximum concentration (Tmax) | Tmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for TAb: Area under the concentration-time curve (AUC) | AUC will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for TAb: Trough concentration (Ctrough) | Ctrough will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for TAb: Terminal or apparent terminal half-life (t1/2) | t1/2 will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for TAb: Systemic clearance (CL) | CL will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for antibody-drug conjugate (ADC): Cmax | Cmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for ADC: Tmax | Tmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for ADC: AUC | AUC will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for ADC: Ctrough | Ctrough will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for ADC: t1/2 | t1/2 will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for ADC: CL | CL will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for Monomethyl Auristatin E (MMAE): Cmax | Cmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for MMAE: Tmax | Tmax will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for MMAE: AUC | AUC will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for MMAE: Ctrough | Ctrough will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for MMAE: t1/2 | t1/2 will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| PK parameter for MMAE: CL | CL will be derived from the PK blood samples collected. | Dose 1 and Dose 3: pre-dose, 0.5 hour, 1 hour, 1.5 hours, 10 hours, 24 hours, 48 hours, 72 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after start of infusion. Dose 2: pre-dose. | 
| Immunogenicity assessment | Assessment of anti-RC108 antibodies | Dose 1 to Dose 3: pre-dose, and 504 hours after start of infusion (Dose 3 only) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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c-Met positive, solid tumor