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RC48 Combined With Toripalimab and Radiotherapy for Bladder Sparing Treatment in MIBC

Primary Purpose

Muscle Invasive Bladder Cancer, HER2 Expression, Radiotherapy

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Disitamab Vedotin and Toripalimab
Sponsored by
RenJi Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Muscle Invasive Bladder Cancer focused on measuring Muscle Invasive Bladder Cancer, HER2 expression, Radiotherapy, PD-1, ADC, Bladder Sparing

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria: ECOG PS: 0~1;Subjects underwent TURBT surgery or partial cystectomy and imaging diagnosis, which was determined to be muscular infiltrating urothelial carcinoma of the bladder (urothelial carcinoma being the main pathological component: 50%) and planned to undergo radical total cystectomy + lymph node dissection + urine flow diversion; cT2-T4a N0 M0 (CT/MRI ± PET/CT);Undergo TURBT or partial cystectomy;Tissue examination specimens with TURBT or partial cystectomy;Expected survival ≥3 months;Immunohistochemical staining of tissue after final TURBT or partial cystectomy showed IHC 2+ or 3+;The major organs are functioning normally, the following criteria are met: The blood routine examination criteria should meet (no blood transfusion and no treatment with granulocyte colony stimulating factor within 14 days before enrollment) : i. Absolute count of neutrophils (ANC) ≥1,000/mm3 ii. Platelet count ≥75,000/mm3 iii. Hemoglobin ≥ 8.0g /dL Liver function: i. Total bilirubin ≤1.5× prescribed ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5×ULN ii. Upper limit of normal values (ULN) ≤2.5 times of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) Note: ≤1.5× ULN (This criterion only applies to patients who have not received anticoagulant therapy; Patients receiving anticoagulant therapy should keep anticoagulants within therapeutic limits); Kidney function: The Cockcroft-Gault formula was used to determine the creatinine clearance (CrCl) > 30 mL/min. Subjects (or their legal representatives) must sign an informed consent form (ICF) indicating that they understand the purpose and procedures of the study and are willing to participate in the study; Fertile women must have a negative pregnancy test result (beta-hCG) (urine or serum) within 7 days before the study drug is first administered. Exclusion criteria: Previously received anti-PD-1, anti-PD-L1, anti-PD-L2 therapy, including adjuvant therapy stage;Known allergy to recombinant humanized anti-PD-1 monoclonal antibody drugs and their components;Those who had received other antitumor therapy (including corticosteroid therapy, immunotherapy) or participated in other clinical studies within 4 weeks prior to study therapy, or had not recovered from previous toxicity (except for 2 degree hair loss and 1 degree neurotoxicity);Pregnant or lactating woman;HIV positive;People with active hepatitis B or C;A history of definite active tuberculosis;Have active autoimmune diseases requiring systemic treatment within the past 2 years (e.g., use of disease-regulating drugs, corticosteroids, or immunosuppressive drugs) that allow for relevant replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for renal or pituitary insufficiency);Other serious, uncontrolled concomitant diseases that may affect protocol adherence or interfere with interpretation of results, These include active opportunistic or progressive (severe) infections, uncontrolled diabetes, cardiovascular disease (heart failure of Grade Ⅲ or Ⅳ as defined by the New York Heart Association scale, heart block of degree Ⅱ or higher, myocardial infarction within the past 6 months, unstable arrhythmia or unstable angina, cerebral infarction within 3 months, etc.), or pulmonary disease (interstitial pneumonia, History of obstructive pulmonary disease and symptomatic bronchospasm);Those who received the live vaccine within 4 weeks before treatment began;Previously received allogeneic hematopoietic stem cell transplantation or solid organ transplantation;Major surgical procedures (excluding diagnostic surgery) within 4 weeks prior to the start of treatment;Those who have a history of psychotropic substance abuse and cannot abstain or have a history of mental disorders;A large amount of pleural fluid or ascites with clinical symptoms or symptomatic management;Have had other unhealed malignancies in the past 5 years, excluding those that are apparently cured or curable, such as basal or squamous cell skin cancer, localized low-risk prostate cancer, carcinoma in situ of the cervix or carcinoma in situ of the breast; Remarks: Patients with localized low-risk prostate cancer (defined as stage ≤T2b, Gleason score ≤7, and PSA≤20ng/mL at the time of prostate cancer diagnosis (as measured) who had received radical therapy and had no biochemical recurrence of prostate specific antigen (PSA) were eligible to participate in this study);Urothelial carcinoma associated with upper urinary tract (renal pelvis and ureteral urothelial carcinoma);Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that, according to the investigator, may increase the risks associated with study participation or may interfere with the interpretation of the study results

Sites / Locations

  • Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RC48+Toripalimab+Radiotherapy

Arm Description

RC48: 2.0 mg/kg, Q2W, iv; Toripalimab: 3mg/kg, Q2W, iv; Radiotherapy: total dose was greater than 50Gy (about 30 times).

Outcomes

Primary Outcome Measures

Safety
Adverse events will be defined according to NCI CTCAE, Version 5.0

Secondary Outcome Measures

Percent of Patients With Complete Response (CR)
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
Percent of Patients With Complete Response (CR)
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
Percent of Patients With Complete Response (CR)
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
1-yr and 2-yr Bladder-intact Event-free Survival (BI-EFS)
Defined by time from enrollment to the occurrence of one of the following events: disease progression, switch to other therapy, intolerant adverse events, or death
Recurrence Free Survival (RFS)
Defined by time from day of first treatment to recurrent NMIBC based on cystoscopy, cytology and/or biopsy.
Overall Survival (OS)
Defined by time from day of first treatment to death
Cancer-Specific Survival
Defined by time from day of first treatment to metastatic bladder cancer

Full Information

First Posted
July 31, 2023
Last Updated
August 29, 2023
Sponsor
RenJi Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05979740
Brief Title
RC48 Combined With Toripalimab and Radiotherapy for Bladder Sparing Treatment in MIBC
Official Title
RC48 Combined With PD-1 and Radiotherapy as Bladdersparing Therapy in Patients With Muscular Infiltrating Bladder Uroepithelial Carcinoma With Limited HER-2 Expression Following Maximum Electrical Resection or Partial Cystectomy
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 1, 2023 (Actual)
Primary Completion Date
December 13, 2023 (Anticipated)
Study Completion Date
February 13, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
RenJi Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a prospective, open, single-center clinical study of RC48 combined with PD-1 and radiotherapy as bladder-preserving therapy in patients with muscular invasive bladder uroepithelial carcinoma with high HER-2 expression (IHC 2+ or 3+). The study was conducted in accordance with the Good Practice for Clinical Trials of Pharmaceutical Products (GCP). Six patients were enrolled in this study. Each patient received RC48 injection [2.0 mg/kg, Q2W, iv] and Toripalimab injection [3mg/kg, Q2W, iv] for 1~2 cycles, and radiotherapy at the second or third cycle. The total dose of bladder irradiation field was greater than 50Gy (about 30 times), and the safety monitoring of the subjects was conducted within 28 days after receiving the study drug treatment for the first time. Adverse events were graded using the National Cancer Institute (NCI) Standard for the Assessment of Common Terminology for Adverse Events (CTCAE) Version 5.0 guidelines, and the occurrence of DLT in patients was observed. If the subject does not complete the safety assessment for the tolerance observation period for non-dose tolerance reasons, a new subject will be replaced.
Detailed Description
This is a prospective, open, single-center clinical study of RC48 in combination with PD-1 and radiotherapy as bladder-preserving therapy in patients with muscular invasive bladder uroepithelial carcinoma with high HER-2 expression (IHC 2+ or 3+). The study was conducted in accordance with the Good Practice for Clinical Trials of Pharmaceutical Products (GCP). Subjects undergo maximum transurethral electrocystotomy (TURBT) or partial cystectomy, imaging diagnosis, and pre-treatment biological samples of blood, urine, and biopsy tissue. The researchers determined that localized invasive bladder cancer with high HER-2 expression could be treated with bladder conserving therapy with maximum TURBT. Patients will receive RC48 combined with PD-1 and radiotherapy after TURBT surgery. Subjects should receive RC48 combined with PD-1 every two weeks for 12 treatment cycles and radiotherapy (bladder irradiation field greater than 50Gy). After completion of the above treatment, tumor site pathology, imaging, and exfoliation cytology are obtained with diagnostic TURBT for tumor evaluation to determine complete remission, and the first tumor efficacy evaluation is performed after completion of radiotherapy (12 weeks after treatment) and every 12 weeks after completion of radiotherapy. Patients with radiotherapy intolerance (as assessed by the investigator) were discontinued directly. Adverse events will be monitored during the study period and graded using the National Cancer Institute's (NCI) Standards for the Assessment of Adverse Events in General Terminology (CTCAE) Version 5.0 guidelines. The safety assessment was carried out after 28 days. Subjects who discontinue medication for reasons other than disease progression will be followed for post-treatment disease status until subjects begin other antitumor therapy, develop disease progression, withdraw informed consent, die, or end of the study, whichever occurs first. All subjects will be followed up via outpatient cystoscopy (every 3 months within 1 year of withdrawal and every 6 months after 1 year) until subject's death, withdrawal of informed consent, or the end of the study, whichever occurs first. Participation in this study will require participants to submit a TURBT tumor tissue specimen or a newly obtained tumor lesion biopsy from prior untreated radiation therapy for biomarker and efficacy correlation evaluation. Blood and urine samples from patients will be collected during the treatment to explore potential biomarkers correlated to the treatment efficacy and patient response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Muscle Invasive Bladder Cancer, HER2 Expression, Radiotherapy, PD-1, Antibody-drug Conjugates
Keywords
Muscle Invasive Bladder Cancer, HER2 expression, Radiotherapy, PD-1, ADC, Bladder Sparing

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
RC48+Toripalimab+Radiotherapy
Arm Type
Experimental
Arm Description
RC48: 2.0 mg/kg, Q2W, iv; Toripalimab: 3mg/kg, Q2W, iv; Radiotherapy: total dose was greater than 50Gy (about 30 times).
Intervention Type
Drug
Intervention Name(s)
Disitamab Vedotin and Toripalimab
Other Intervention Name(s)
RC48, JS001
Intervention Description
Each patient received RC48 injection [2.0 mg/kg, Q2W, iv] and Toripalimab injection [3mg/kg, Q2W, iv] for 1~2 cycles, and Radiotherapy radiotherapy at the second or third cycle. The total dose of bladder irradiation field was greater than 50Gy (about 30 times), and the safety monitoring of the subjects was conducted within 28 days after receiving the study drug treatment for the first time.
Primary Outcome Measure Information:
Title
Safety
Description
Adverse events will be defined according to NCI CTCAE, Version 5.0
Time Frame
Up to 28 days
Secondary Outcome Measure Information:
Title
Percent of Patients With Complete Response (CR)
Description
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
Time Frame
Up to 3 months
Title
Percent of Patients With Complete Response (CR)
Description
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
Time Frame
Up to 12 months
Title
Percent of Patients With Complete Response (CR)
Description
CR is defined by negative cystoscopy, urine cytology, and bladder biopsies.
Time Frame
Up to 24 months
Title
1-yr and 2-yr Bladder-intact Event-free Survival (BI-EFS)
Description
Defined by time from enrollment to the occurrence of one of the following events: disease progression, switch to other therapy, intolerant adverse events, or death
Time Frame
Up to 24 months
Title
Recurrence Free Survival (RFS)
Description
Defined by time from day of first treatment to recurrent NMIBC based on cystoscopy, cytology and/or biopsy.
Time Frame
Up to 24 months
Title
Overall Survival (OS)
Description
Defined by time from day of first treatment to death
Time Frame
Up to 24 months
Title
Cancer-Specific Survival
Description
Defined by time from day of first treatment to metastatic bladder cancer
Time Frame
Up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: ECOG PS: 0~1;Subjects underwent TURBT surgery or partial cystectomy and imaging diagnosis, which was determined to be muscular infiltrating urothelial carcinoma of the bladder (urothelial carcinoma being the main pathological component: 50%) and planned to undergo radical total cystectomy + lymph node dissection + urine flow diversion; cT2-T4a N0 M0 (CT/MRI ± PET/CT);Undergo TURBT or partial cystectomy;Tissue examination specimens with TURBT or partial cystectomy;Expected survival ≥3 months;Immunohistochemical staining of tissue after final TURBT or partial cystectomy showed IHC 2+ or 3+;The major organs are functioning normally, the following criteria are met: The blood routine examination criteria should meet (no blood transfusion and no treatment with granulocyte colony stimulating factor within 14 days before enrollment) : i. Absolute count of neutrophils (ANC) ≥1,000/mm3 ii. Platelet count ≥75,000/mm3 iii. Hemoglobin ≥ 8.0g /dL Liver function: i. Total bilirubin ≤1.5× prescribed ULN or direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5×ULN ii. Upper limit of normal values (ULN) ≤2.5 times of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) Note: ≤1.5× ULN (This criterion only applies to patients who have not received anticoagulant therapy; Patients receiving anticoagulant therapy should keep anticoagulants within therapeutic limits); Kidney function: The Cockcroft-Gault formula was used to determine the creatinine clearance (CrCl) > 30 mL/min. Subjects (or their legal representatives) must sign an informed consent form (ICF) indicating that they understand the purpose and procedures of the study and are willing to participate in the study; Fertile women must have a negative pregnancy test result (beta-hCG) (urine or serum) within 7 days before the study drug is first administered. Exclusion criteria: Previously received anti-PD-1, anti-PD-L1, anti-PD-L2 therapy, including adjuvant therapy stage;Known allergy to recombinant humanized anti-PD-1 monoclonal antibody drugs and their components;Those who had received other antitumor therapy (including corticosteroid therapy, immunotherapy) or participated in other clinical studies within 4 weeks prior to study therapy, or had not recovered from previous toxicity (except for 2 degree hair loss and 1 degree neurotoxicity);Pregnant or lactating woman;HIV positive;People with active hepatitis B or C;A history of definite active tuberculosis;Have active autoimmune diseases requiring systemic treatment within the past 2 years (e.g., use of disease-regulating drugs, corticosteroids, or immunosuppressive drugs) that allow for relevant replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for renal or pituitary insufficiency);Other serious, uncontrolled concomitant diseases that may affect protocol adherence or interfere with interpretation of results, These include active opportunistic or progressive (severe) infections, uncontrolled diabetes, cardiovascular disease (heart failure of Grade Ⅲ or Ⅳ as defined by the New York Heart Association scale, heart block of degree Ⅱ or higher, myocardial infarction within the past 6 months, unstable arrhythmia or unstable angina, cerebral infarction within 3 months, etc.), or pulmonary disease (interstitial pneumonia, History of obstructive pulmonary disease and symptomatic bronchospasm);Those who received the live vaccine within 4 weeks before treatment began;Previously received allogeneic hematopoietic stem cell transplantation or solid organ transplantation;Major surgical procedures (excluding diagnostic surgery) within 4 weeks prior to the start of treatment;Those who have a history of psychotropic substance abuse and cannot abstain or have a history of mental disorders;A large amount of pleural fluid or ascites with clinical symptoms or symptomatic management;Have had other unhealed malignancies in the past 5 years, excluding those that are apparently cured or curable, such as basal or squamous cell skin cancer, localized low-risk prostate cancer, carcinoma in situ of the cervix or carcinoma in situ of the breast; Remarks: Patients with localized low-risk prostate cancer (defined as stage ≤T2b, Gleason score ≤7, and PSA≤20ng/mL at the time of prostate cancer diagnosis (as measured) who had received radical therapy and had no biochemical recurrence of prostate specific antigen (PSA) were eligible to participate in this study);Urothelial carcinoma associated with upper urinary tract (renal pelvis and ureteral urothelial carcinoma);Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that, according to the investigator, may increase the risks associated with study participation or may interfere with the interpretation of the study results
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Haige Chen
Phone
02168383575
Email
kirbyhaige@aliyun.com
First Name & Middle Initial & Last Name or Official Title & Degree
Ruiyun Zhang
Phone
02168383575
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Haige Chen
Organizational Affiliation
RenJi Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Renji Hospital, School of Medicine, Shanghai Jiao Tong University
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200127
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
haige chen, M.D
Phone
86-21-68383575
Email
kirbyhaige@aliyun.com
First Name & Middle Initial & Last Name & Degree
Haige Chen, M.D

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

RC48 Combined With Toripalimab and Radiotherapy for Bladder Sparing Treatment in MIBC

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