Trial Title:
RC48 Combined With Tislelizumab for Bladder Sparing Treatment in NMIBC With BCG Treatment Failure and HER2 Expression
NCT ID:
NCT05957757
Condition:
Non-Muscle Invasive Bladder Cancer
HER2
Conditions: Official terms:
Urinary Bladder Neoplasms
Non-Muscle Invasive Bladder Neoplasms
Tislelizumab
Disitamab vedotin
Conditions: Keywords:
Non-Muscle Invasive Bladder Cancer
HER2 expression
BCG Failure
Unsuitable or refused to radical cystectomy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
To study the safety and efficacy of RC48 combined with Tislelizumab in HER2 expression
high grade non muscle invasive bladder cancer patients who failed BCG therapy and refused
cystectomy.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
RC48
Description:
RC48 was scheduled to be administered at a dose of 2.0mg/kg every 2 weeks, with the first
dose on day 1 of the first cycle.
The drug is diluted with normal saline and administered by intravenous drip for one hour.
Arm group label:
RC48+Tislelizumab
Other name:
Disitamab Vedotin
Intervention type:
Drug
Intervention name:
Tislelizumab
Description:
Tislelizumab was administered at a dose of 200 mg every 3 weeks, with the first dose on
day 1 of the first 21-day cycle.
The drug is diluted with normal saline and administered by intravenous drip for one hour.
Arm group label:
RC48+Tislelizumab
Summary:
This is a prospective, open, single-center clinical study of anti-HER2-ADC combined with
PD-1 monoclonal antibody for bladder sparing treatment in non-muscular invasive bladder
cancer (NMIBC) patients with HER2-expressing. The study was conducted in accordance with
the Good Clinical Practice (GCP). Approximately 20 subjects will be enrolled to evaluate
the efficacy and safety of RC48 (RC48 2.0 mg/kg intravenously administered every two
weeks) combined with Tislelizumab (Tislelizumab 200 mg intravenously administered every
three weeks).
Subjects undergo Transurethral resection of bladder tumor (TURBT), imaging diagnosis and
pre-treatment biological samples of blood, urine and biopsy tissue.
The study will include high-risk NMIBC patients who express HER2, fail after BCG
treatment, but refuse to undergo cystectomy or do not meet the requirements for
cystectomy.
Subjects will receive RC48 and Tislelizumab for two years. BI-DFS were evaluated by
cystoscopy, histopathologic examination, laboratory examination, and imaging examination
after treatment, and tumor efficacy was evaluated when clinical studies reached the
number of subjects specified in the protocol for efficacy evaluation.
Detailed description:
For Non-muscle invasive bladder cancer (NMIBC), Transurethral resection of bladder tumor
(TURBT) is the primary treatment. TURBT relapses within 12 months after surgery in 10% to
67% of patients, and postoperative bladder perfusion therapy (including chemotherapy and
Immunotherapy) significantly reduces the recurrence rate. However, about 30%-40% of
patients will relapse after BCG treatment. Radical cystectomy is the standard of care for
patients who do not respond to BCG treatment and have high grade NMIBC. However, radical
cystectomy has a high incidence of postoperative complications (up to 60%) and a negative
impact on HRQoL. These complications occur even in high-volume centers of excellence,
whether open or minimally invasive, and the mortality rate from the surgery itself is
about 3%. Therefore, some patients refuse to undergo radical cystectomy. In addition,
some patients are medically unfit for surgery due to age, functional status, American
Society of Anesthesiologists classification, comorbiditions, body mass index, and other
factors. Although penerubicin is the only bladder sparing drug approved by the U.S. Food
and Drug Administration (FDA) for patients who are not suitable for or unwilling to
undergo cystectomy, BCG refractory, and with CIS NMIBC, no legally marketed penerubicin
drug is available in China. Therefore, new treatments are needed to prevent invasive
bladder cancer from affecting the entire bladder.
In recent years, immunocheckpoint inhibitors represented by PD-1/PD-L1 have been proved
to be a promising means of tumor immunotherapy, which has made a breakthrough in the
treatment of advanced urothelial carcinoma, and become the main choice for the treatment
of advanced urothelial carcinoma. Immunocheckpoint inhibitors also showed positive
results in patients who did not respond to BCG treatment during perioperative and
perioperative periods.Therefore, immunotherapy is expected to be an alternative bladder
sparing therapy for high-risk NMIBC patients.The anti-HER2-ADC drug RC48 also achieved
significant efficacy in HER2-overexpressed advanced urothelial carcinoma, and its
combination with PD-1 monoclonal antibody Toripalimab was more effective in the
first-line treatment of advanced metastatic urothelial carcinoma. Therefore, RC48
combined with PD-1 can be used as a potential treatment for bladder sparing in patients
with NMIBC.
In NMIBC patients with HER2 expression, ADC drugs can target tumor cells and deliver
cytotoxic drugs with greater safety than chemotherapy. In addition, the application of
anti-HER2-ADC drugs combined with PD-1 in bladder sparing therapy is still lacking in
experience and related studies. Therefore, we plan to conduct a study on bladder
preservation therapy for patients with HER2-expressing NMIBC treated with ADC drugs
combined with PD-1 monoclonal antibody, so as to preserve the bladder function of
patients while controlling tumor recurrence and ensuring their quality of life.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. ≥18 years old
2. Histologically confirmed recurrent, non-muscle invasive bladder cancer;
1. Histopathology: Patients with any variant urothelial cell carcinoma (UCC)
(i.e., squamous and/or glandular epithelial differentiation UCC, UCC with
micropapillary changes, nest variant UCC, plasmacytoid UCC, neuroendocrine UCC,
and sarcomatoid UCC) were enrolled. The presence of any lymphatic infiltration
(LVI) is considered evidence of high risk.
2. Papillary carcinoma must be a high-risk disease defined as a high grade Ta/T1
lesion. In addition, subjects must have all visible tumors completely removed
prior to initial administration of the study drug, as documented at baseline
cystoscopy. Cytological results for high-grade urothelial carcinoma must be
negative prior to initial administration of the investigational drug.
3. CIS does not require complete excision, but must be completely excised with
coexisting papillary carcinoma prior to enrollment and documented at baseline
cystoscopy. Negative urine cytology for malignant cells is not required.
3. When BCG recurred after treatment, the presence of HER2 expression was detected by
IHC in the pathology department of our hospital
4. BCG treatment failure included no response to BCG treatment and relapse after
inadequate BCG treatment
1. Subjects without response after adequate BCG treatment must meet at least one
of the following criteria: 1) Persistent or recurrent simple CIS with or
without recurrent Ta/T1 (non-invasive papillary carcinoma/tumor invasion of
subepithelial connective tissue) disease within 12 months after completion of
adequate BCG treatment; 2) Recurrent high-grade Ta/T1 disease occurred within 6
months after completion of adequate BCG treatment; 3) T1 high-grade disease was
present at the first disease assessment after completion of a BCG induction
course. Adequate BCG treatment (minimum treatment requirement) : at least 5 out
of 6 full dose treatments were received during the initial induction course and
at least 1 maintenance treatment within 6 months (one full dose per week and 2
out of 3 completed treatments); Or received at least 5 out of 6 full doses in
the initial induction course and at least 2 out of 6 full doses in the second
induction course.
2. Relapse after inadequate BCG treatment: Subjects must meet the following
criteria: Recurrence of high-grade Ta/T1 disease within 12 months of completion
of BCG treatment (as defined below): Previous inadequate BCG treatment (minimum
treatment requirement) included receiving at least 5 out of 6 full dose
treatments during the initial induction course. Or received at least 5 out of 6
full dose treatments during the initial induction course and at least 1
maintenance treatment (once a week and 2 out of 3 completed treatments) within
6 months. One half or one third of the dose is allowed during maintenance
treatment.
5. To refuse or be unsuitable for radical cystectomy
6. ECOG 0~1
7. The major organs are functioning normally, the following criteria are met:
(1) 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 (2) 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); (3) Kidney function: The Cockcroft-Gault
formula was used to determine the creatinine clearance (CrCl) > 30 mL/min.
8. 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; 9. 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:
1. Confirmed by histology of muscular layer infiltration (T2 or higher level) bladder
urothelial carcinoma.
2. Histopathological examination revealed any bladder small cell composition, pure,
pure squamous cell carcinoma or simple squamous adenocarcinoma CIS;
3. Received other PD - 1 / PD - L1 inhibitor and/or HER2 inhibitor;
4. Active malignancies other than the disease being treated (i.e., disease progression
within the last 24 months or requiring a change in treatment). Only the following
special circumstances are allowed: i. Skin cancer that has been treated and
completely cured within the last 24 months; ii. Adequately treated lobular carcinoma
in situ (LCIS) and ductal CIS; iii. A history of local breast cancer and receiving
antihormonal drugs or a history of local prostate cancer (N0M0) and receiving
androgen blocking therapy.
5. History of uncontrolled cardiovascular disease, including: 1) any of the following
in the past 3 months: unstable angina, myocardial infarction, ventricular
fibrillation, toroidal ventricular tachycardia, cardiac arrest, or known congestive
New York Heart Association Class III-IV heart failure, cerebrovascular accident, or
transient ischemic attack; 2) Prolonged QTc interval confirmed by ECG evaluation
during screening (Fridericia; QTc > 480 ms); 3) Pulmonary embolism or other venous
thromboembolism within the past 2 months.
6. Pregnancy or lactation women;
7. Known human immunodeficiency virus (HIV) infection, unless the subjects in the past
six months or longer had accepted the stability of antiretroviral therapy (art), and
no opportunistic infections occurred in the past 6 months, and over the past six
months the CD4 count of > 350;
8. Have evidence of active hepatitis B or hepatitis C infection (for example, a history
of hepatitis C but hepatitis C virus polymerase chain reaction detection results and
normal subjects of hepatitis B surface antigen antibody positive hepatitis B can
groups);
9. Has yet to recover from past the toxic effects of anticancer therapy (except no
clinical significance of toxic effects, such as hair loss, skin discoloration,
neuropathy, and hearing impairment).
10. Wound healing delay, defined as the skin/decubitus ulcer, chronic leg ulcer, had
known gastric ulcer or incision to heal.
11. 1 cycle day 1 major surgery within 4 weeks before (don't think TURBT belong to major
surgery).
12. Other patients assessed by the investigator as unsuitable for participation in the
study.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Ethics Committee of Shanghai Renji Hospital
Address:
City:
Shanghai
Country:
China
Status:
Recruiting
Contact:
Last name:
Qi Lu
Phone:
+86021-68383364
Email:
rjllb3364@163.com
Start date:
August 5, 2023
Completion date:
June 8, 2026
Lead sponsor:
Agency:
RenJi Hospital
Agency class:
Other
Collaborator:
Agency:
RemeGen Co., Ltd.
Agency class:
Industry
Collaborator:
Agency:
BeiGene
Agency class:
Industry
Source:
RenJi Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05957757
