A Study of RC148 in Patients With Locally Advanced Unresectable or Metastatic Malignant Solid Tumors

Study Overview
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Brief Summary
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This trial is to evaluate the safety, tolerability, maximum tolerated dose (MTD) / maximum administered dose (MAD), pharmacokinetics (PK), pharmacodynamics, immunogenicity and recommended Phase 2 dose (RP2D) of RC148 in participants with locally advanced unresectable or metastatic solid tumors.In addition, the preliminary anti-tumour efficacy of RC148 as single agent will be assessed.

Official Title
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Safety, Tolerability, Pharmacokinetics, and Efficacy of RC148 in Patients With Locally Advanced Unresectable or Metastatic Solid Tumors: an Open-Label, Multicenter, Phase I Trial

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: RC148


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be able to provide documented voluntary informed consent. Male or female participants ≥ 18 years. Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. The expected survival period exceeds 12 weeks. At least one target lesion that can be measured per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.(For patients with prior radiotherapy, radiotherapy-treated lesions may be considered target lesions if they are measurable according to RECIST v1.1 criteria and there is evidence of significant progression after radiotherapy) Histologically or cytologically documented advanced or metastatic solid tumor that is refractory/relapsed to standard therapies, or for which no effective standard therapy is available, or the subject refuses standard therapy. Participants agree to provide pre-treatment archived /biopsy tumour samples (8-10 tissue slides) for retrospective programmed cell death protein 1 (PD-1)Expression level and MSI/MMR status related tests.Tumor specimen for marker detection should be from the most recent timepoint before entering the trial. Only when archived samples cannot be obtained, the biopsy will be considered at screening. Fresh tumour biopsies will NOT be considered if significant risk procedures are required per the discretion of the Investigator. Adequate bone marrow, liver, and renal function defined as: absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet ≥ 100 × 10^9/L, haemoglobin ≥ 90 g/L, serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT, AST ≤ 2.5 × ULN (≤ 5 × ULN when there is known liver metastasis), serum creatinine ≤ 1.5 × ULN, International normalized ratio (INR) ≤ 1.5 × ULN, Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. Urinalysis results for urinary protein <++; Subjects for whom urine protein ≥++ by urine test strip at baseline A 24-hour urine collection should be performed and the amount of protein in the urine over a 24-hour period should be <1g; 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 contraceptive device. Exclusion Criteria: Pregnant or lactating. Diagnosed active hepatitis B infection (defined as positive of hepatitis B surface antigen (HBsAg) and hepatitis B deoxyribonucleic acid [DNA]≥500IU/ml), active hepatitis C infection (defined as presence of hepatitis C ribonucleic acid [RNA]), and human immunodeficiency virus (HIV) infection (defined as positive HIV test) during the screening period. Received live attenuated vaccination within 28 days prior to the first dose of RC148 Participant with a history of other acquired/congenital immunodeficiency diseases or organ transplantation. Participant who received prior anti-PD-1, anti- programmed cell death protein ligand 1 (anti-PD-L1), anti-cytotoxic T lymphocyte-associated (CTLA)-4 or any other immunotherapy or immune-oncology agent within 28 days of commencing treatment with RC148 or experienced a toxicity that led to permanent discontinuation of prior immunotherapy. Participant who had participated in other clinical trials and received study drug within 4 weeks before the first administration of IP. Allergic constitution or allergic to known research drug active ingredients or excipient. Participant who are under the treatment of anticoagulant drugs (e.g., warfarin, apixaban, and heparin). Participants using prophylactic doses of heparin (e.g., low-molecular-weight heparins [LMWH]) are eligible in the study. Participant undergo any anti-tumour therapy, including surgery, chemotherapy, radiotherapy and biological therapy within 4 weeks prior to the first administration of IP,or Chinese traditional medicine for an antitumor indication within 2 weeks prior to first drug administration, or palliative radiotherapy for bone/other solitary metastases within 2 weeks prior to the first administration of IP. Previous adverse reactions resulting from previous anti-tumour therapies, which have not returned to Grade 0 or 1 according to NCI-CTCAE v5.0 (except alopecia) at screening. There are clinical symptoms of fluid in the third space (e.g., large amounts of pleural fluid or ascites). A clinically significant active infection judged by the investigator(IP begins 2 weeks after completion of anti-infective treatment). Comorbidities that may seriously endanger the participant's safety or affect the completion of the study, such as gastrointestinal bleeding (within 4 weeks prior to the screening period), History of hemoptysis (single hemoptysis > 2.5 mL of bright red blood) within 4 weeks prior to screening，peptic ulcer (within 4 weeks prior to the screening period), intestinal obstruction, intestinal paralysis, interstitial pneumonia, pulmonary fibrosis, kidney failure,Severe esophagogastric fundic varices and uncontrolled diabetes. QT interval corrected by Fridericia's formula (QTcF) interval > 450 ms( male） and (QTcF) interval > 470 ms（ femal (based on the mean value of the triplicate screening electrocardiogram [ECG]); family or personal history of long/short QT syndrome; history of ventricular arrhythmia deemed clinically significant by the investigator, or currently receiving antiarrhythmic drug treatment, or implantation of arrhythmia defibrillation device. Have experienced arterial/venous thromboembolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis and pulmonary embolism within 1 year prior to the initiation of study treatment; History of myocardial infarction within 6 months prior to the screening period, severe or unstable angina pectoris, coronary or peripheral artery bypass grafting, heart failure ≥ 3 (New York Heart Association), or uncontrolled hypertension. Participants with a condition requiring systemic treatment with either corticosteroid (> 10 mg daily) or other immunosuppressive medications within 2 weeks of first IP administration. Participants with active central nervous system (CNS) metastases. Participants with treated CNS metastases are permitted on study if the CNS metastases have been clinically stable for at least 4 weeks prior to treatment initiation and baseline scans show no evidence of new or enlarged lesions and meanwhile participant does not have leptomeningeal disease.For Carcinomatous Meningitis, regardless of whether the clinical status is stable or not, they should be excluded; Have undergone major surgeries within 4 weeks prior to study treatment and have not recovered yet; History or presence of uncontrolled mental illness at the discretion of the Investigator, which may place the participant at increased risk of safety/tolerability issues. The participant is, in the opinion of the investigator, expected to be non-compliant with critical trial procedures and is not willing or able to adhere to the trial requirements in the future. Participants who are not appropriate for this clinical trial at the discretion of the investigator. Previously received dual anti-tumor drugs targeting both VEGF/VEGFR and PD-1/PD-L1. tumor drugs; Screening stage imaging shows tumor invasion of large blood vessels. Other malignancies within 5 years prior to the start of study dosing, except: malignancies that are expected to resolve with treatment (including, but not limited to, adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated by radical surgery)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RC148<br>Participants will be allocated to one of the following dose groups:1.0, 3.0, 10.0, 20.0, and 30.0mg/kg, and receive a treatment of RC148 followed by 28 days of dose limited toxicity (DLT) observation period. | Drug: RC148<br>* RC148 is a bispecific antibody, targeting programmed death-1(PD-1) and Vascular endothelial growth factor(VEGF).<br>* Other names: RC148 for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose(MTD)/Maximum administered dose(MAD) | MTD/MAD based on number of Dose limiting toxicity (DLT) | Subjects will be treated and observed for DLT through the end of the first cycle (Days 1-28) | 
| 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 RC148 treatment | 28 days after first treatment | 
| The incidence and severity of adverse events (AE) | Adverse events was assessed by investigator(s) according to NCI-CTCAE v5.0 | From the day of ICF sign to 28/90 days after the day of the last treatment | 
| Recommended Phase 2 dose(RP2D) | The RP2D may be selected as 1 dose level lower than the MTD and will be determined in discussion with the safety monitoring committee based on all available data | 28 days or 1cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Activity of RC148 by Overall Response Rate(ORR) | Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) | 15 months | 
| DCR | Disease Control Rate was defined as the percentage of participants with a CR or PR or stable disease(SD) | 15 months | 
| 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 | 
| 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 | 
| Pharmacokinetics (PK) parameter: Maximum concentration (Cmax) | Cmax will be derived from the PK blood samples collected. | 15 months | 
| PK parameter: Time to maximum concentration (Tmax) | Tmax will be derived from the PK blood samples collecte | 15 months | 
| PK parameter: Terminal or apparent terminal half-life (t1/2) | t1/2 will be derived from the PK blood samples collected. | 15 months | 
| PK parameter: Area under the concentration-time curve (AUC) | AUC will be derived from the PK blood samples collected. | 15 months | 
| PK parameter:Systemic clearance (CL) | CL will be derived from the PK blood samples collected. | 15 months | 
| PK parameter: Mean residence time (MRT) | MRT will be derived from the PK blood samples collected. | 15 months | 
| PK parameter: Vz | Vz will be derived from the PK blood samples collected. | 15 months | 
| PK parameter: λz | λz will be derived from the PK blood samples collected. | 15 months | 
| Immunogenicity assessment | blood samples will be collected to test the presence anti-RC148 antibodies | 15 months |