A Phase Ib/II Prospective Study to Evaluate the Safety and Efficacy of the Combination of Neoadjuvant Palbociclib and Tislelizumab in Platinum-refractory cT2-4aN0M0 Bladder Urothelial Carcinoma.
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 36
- Locations
- 8
- Primary Endpoint
- Phase I: The safety dose of the combination of Tislelizumab and Palbociclib
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
- •Aged over 18 years on day of signing informed consent
- •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.
- •Patients with mutations or copy number variation (CNV) alterations, such as CDKN2A, CDKN2B CNV deletion, indicating the activation of cell cycle-related pathways.
- •ECOG Performance Status 0 or 1
- •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
- •Patients will receive radical cystectomy following neoadjuvant therapy as assessed by investigator, meet surgical indication and are willing to receive the surgery.
- •Tumor tissue samples collected during TURBT must be available, and relevant pathological reports are required. Fresh surgical tissue samples or pathological slides are optional
- •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).
Exclusion Criteria
- •Received prior therapies targeting PD-1, PD-L1, PD-L2, CTLA4, or other antibodies or drugs specifically targeting T-cell costimulation or checkpoint pathways.
- •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.
- •Received prior radiotherapy for bladder cancer.
- •Received anticancer drug therapies with the following exceptions:
- •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
- •Local intravesical chemotherapy or immunotherapy must be discontinued at least 1 week before start of the investigational neoadjuvant medication treatment
- •Received major surgery or had major trauma within 28 days prior to enrollment (vascular access placement and TURBT are not considered as major surgeries).
- •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 Exclusion Criteria # 12).
- •Received live vaccines within 28 days prior to enrollment (seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.)
- •Active autoimmune diseases that requires systemic treatment and may impact study treatment as assessed by investigator
Arms & Interventions
Phase Ib clinical trial
Tislelizumab, 200mg q3W, combined with two predefined dose groups of palbociclib: 100mg QD and 125mg QD, separately.
Intervention: Tislelizumab combined with two predefined dose groups of palbociclib (Drug)
Phase II clinical trial
Tislelizumab, 200mg q3W, combined with RP2D dose of palbociclib was selected for phase II clinical trial.
Intervention: RP2D dose Of Tislelizumab combined with palbociclib was selected for phase II clinical trial. (Drug)
Outcomes
Primary Outcomes
Phase I: The safety dose of the combination of Tislelizumab and Palbociclib
Time Frame: 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.
Phase II: Percentage of Participants With Pathological Complete Response(pCR)
Time Frame: 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.
Secondary Outcomes
- Percentage of Participants With Pathological Downstaging(pDS)(24 months)
- Event-free survival (EFS)(24 months)
- overall survival (OS)(24 months)
- Safety and AE(24 months)