Bladder Cancer
Conditions
Keywords
Tislelizumab, Palbociclib, neoadjuvant, bladder cancer
Brief summary
In order to explore the safety and antitumor efficacy of different doses of CDK4/6 inhibitor Palbociclib in combination with the Tislelizumab in platinum-refractory cT2-4aN0M0 bladder urothelial carcinoma, a phase Ib/II study was conducted. This study will adopt a 3+3 design and include two predefined dose groups of palbociclib: 100mg QD, 125mg QD. Initially, Tislelizumab, 200 mg administered by intravenous infusion on Day 1 of each 21-day will be administered in combination. The trial will use the first cycle (28 days) as the observation period for tolerability, observing and evaluating the occurrence of DLTs after medication and determining the maximum tolerated dose/maximum administered dose (MTD/MAD) and recommended phase 2 dose (RP2D) of the combination therapy (30 patients) . This study provide further evidence for improving the efficacy of neoadjuvant treatment forplatinum-refractory cT2-4aN0M0 bladder urothelial carcinoma and to offer new options for precision treatment of bladder cancer.
Interventions
DRUGTislelizumab combined with two predefined dose groups of palbociclib
Tislelizumab, 200mg q3W, combined with two predefined dose groups of palbociclib: 100mg QD and 125mg QD, separately.
DRUGRP2D dose Of Tislelizumab combined with palbociclib was selected for phase II clinical trial.
After the exploration of Tislelizumab, 200mg q3W combined with palbociclib, and the maximal tolerated dose (MTD) was determined, then RP2D dose of Tislelizumab combined with palbociclib was selected for phase II clinical trial.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntarily participate in this study, able to provide written informed consent and can understand and agree to comply with the requirements of the study and schedule of assessments. 2. Aged over 18 years on day of signing informed consent 3. Patients with urothelial bladder cancer, having residual lesions following TURBT surgery, staged cT2-T4aN0M0 as histologically confirmed and radiologically assessed based on the TNM Staging System for Bladder Cancer of American Joint Committee on Cancers (AJCC) ; predominantly histological classification of urothelial carcinoma (at least 50%) for patients with mixed-histology bladder cancer. 4. Patients with mutations or copy number variation (CNV) alterations, such as CDKN2A, CDKN2B CNV deletion, indicating the activation of cell cycle-related pathways. 5. ECOG Performance Status 0 or 1 6. Ineligible for Cisplatin treatment as judged by investigator. Patients who are ineligible for Cisplatin chemotherapy should meet at least one of the following criteria: ECOG performance status \> 1 or Karnofsky performance status 60% to 70%; creatinine clearance less than 60 mL/min; ≥ Grade 2 hearing loss according to NCI-CTCAE v5.0; ≥ Grade 2 neuropathy peripheral according to NCI-CTCAE v5.0; ≥ Grade 3 cardiac failure according to New York Heart Association Cardiac Function Classification 7. Patients will receive radical cystectomy following neoadjuvant therapy as assessed by investigator, meet surgical indication and are willing to receive the surgery. 8. Tumor tissue samples collected during TURBT must be available, and relevant pathological reports are required. Fresh surgical tissue samples or pathological slides are optional 9. Have adequate organ function as indicated by the following screening laboratory values (obtained ≤ 14 days prior to enrollment): a.Patients must not be administered with growth factors ≤ 14 days prior to sampling for the screening tests of: i.Absolute neutrophil count ≥ 1.5 x 109/L ii.Platelets ≥ 90 x 109/L iii.Hemoglobin ≥ 90 g/L b.International normalized ratio or activated partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN). c.Serum total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN, if Gilbert's syndrome or if indirect bilirubin concentrations were suggestive of extrahepatic source of the elevation). e.Aspartate transaminase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 x ULN f.Patients can tolerate major abdominal surgery as suggested by pulmonary function test results 10. Unpregnant females or females of childbearing potential must be willing to use a highly effective contraceptive method for the duration of the study, and ≥ 120 days after the last dose of Tislelizumab or chemotherapy agents, whichever is later, and have a negative urine or serum pregnancy test ≤ 7 days prior to enrollment.
Exclusion criteria
1. Received prior therapies targeting PD-1, PD-L1, PD-L2, CTLA4, or other antibodies or drugs specifically targeting T-cell costimulation or checkpoint pathways. 2. Received other approved systemic anticancer therapies or systemic immunomodulators (including but not limited to interferon, interleukin 2, and tumor necrosis factor) within 28 days prior to enrollment. 3. Received prior radiotherapy for bladder cancer. 4. Received anticancer drug therapies with the following exceptions: 1. For patients who have received prior systemic chemotherapy, a treatment-free interval of at least 12 months from the last dose of chemotherapy until the start of neoadjuvant therapy is required 2. Local intravesical chemotherapy or immunotherapy must be discontinued at least 1 week before start of the investigational neoadjuvant medication treatment 5. Received major surgery or had major trauma within 28 days prior to enrollment (vascular access placement and TURBT are not considered as major surgeries). 6. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days prior to enrollment (HBV infection will be ruled out according to
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Percentage of Participants With Pathological Complete Response(pCR) | 24 months | Pathological evaluation of the resected tumor tissue and regional lymph nodes showed no residual tumor cells, complete disappearance of the tumor lesions, and no evidence of new lesions. |
| Phase I: The safety dose of the combination of Tislelizumab and Palbociclib | 12 months | The study aims to evaluate the safety dose of the combination of Tislelizumab combined with palbociclib in patients with cT2-4aN0M0 bladder cancer. The safety dose was according to 3+3 dose escalation principle. Participants with dose-limiting toxicity (DLT) as assessed by NCI CTC 5.0 and the administered drug dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | 24 months | Event-free survival (EFS) was determined from start date of the first dose of neoadjuvant treatment to date of disease progression, death from any cause, or onset of other tumors. |
| Safety and AE | 24 months | Number of unique patients who had a treatment-related (possible, probable, or definite) adverse event using the Medical Dictionary for Regulatory Activities (MedDRA) terms and graded per NCI-CTCAE v5.0. Number and Grade of patients who had a surgery-related adverse event (surgery-related AE) will be measured according to the Clavien-Dindo classification. |
| overall survival (OS) | 24 months | OS was measured from the date the participant started study to death for any reason. |
| Percentage of Participants With Pathological Downstaging(pDS) | 24 months | The pathological downstaging rate is defined as the evaluation of whether the staging is degraded to ≤ T2 based on the post-surgery pathological findings. The rates of cT2N0 → pT0N0, cT3-4aN0 → pT0N0, cT2N0 → ≤ pT1N0, cT3-4aN0 → ≤ pT1N0 will be calculated, and the 2 sided Clopper-Pearson 95% confidence interval (CI) of pathological downstaging rate will be calculated to assess the precision of the estimated pathological downstaging rate. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Endpoint Analyses | 24 months | To explore biomarkers in urine, blood, and tumor tissues (collected from TURBT) at baseline and tissue samples collected from radical cystectomy. Biomarkers include PD-L1, Ki67 expression in tumor tissues, immune cells profiling and gene expression and tumor mutation profiling. |
Countries
China
Contacts
Primary ContactWenlong Zhong, Ph.D
Outcome results
None listed