Phase Ib/II Trail of Neoadjuvant of Tislelizumab Combined With Palbociclib in Patients With Platinum-refractory Bladder Urothelial Carcinoma

Bladder Cancer Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06364956
• Other study ID #: SYSKY-2024-124-02
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 2024
• Est. completion date: June 2026

Study information

• Verified date: April 2024
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: Wenlong Zhong, Ph.D
• Phone: 020-81338949
• Email: zhongwlong3[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: June 2026
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 Exclusion Criteria # 12).

7. 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.)

8. Active autoimmune diseases that requires systemic treatment and may impact study treatment as assessed by investigator

9. Any condition that requires extensive chronic treatment with either hormones or any other immunosuppressive medications that may impact study treatment as assessed by investigator.

10. With history of potassium, sodium, calcium abnormalities or hypoalbuminemia, interstitial lung disease, pneumonitis or history of uncontrolled systemic diseases, including diabetes, hypertension, cardiovascular diseases (such as active cardiac diseases within 6 months prior to enrollment, including: severe/unstable angina pectoris, myocardial infarction, symptomatic congestive heart failure, and ventricular arrhythmia requiring medical treatment) that may impact study treatment as assessed by investigator.

11. HBV Patients with untreated chronic hepatitis B or hepatitis B virus (HBV) carriers with HBV DNA = 500 IU/mL (2500 copies/mL) cannot be enrolled. Note: inactive hepatitis B surface antigen (HBsAg) carriers and patients who received continuous antiviral treatments and have stable active hepatitis B infection (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. HBV DNA testing will be performed only for patients testing positive for antibody to hepatitis B core antigen (anti-HBc).

12. Patients with active hepatitis C cannot be enrolled. Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening can be enrolled. The HCV RNA test will be performed only for patients testing positive for HCV antibody.

13. History of immunodeficiency (including human immunodeficiency virus [HIV] positive, other acquired, congenital immunodeficiency diseases) or history of allogeneic stem cell transplantation or organ transplantation.

14. Known hypersensitivity to other monoclonal antibodies.

15. Known hypersensitivity to any investigational agents or their excipients.

16. Patients with toxicities or AEs (as a result of any prior treatment) which have not recovered to baseline or stabilized, except for toxicities or AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory abnormalities) as assessed by investigator.

17. Underlying medical conditions or alcohol or drug abuse or dependence that were to be unfavorable for the administration of investigational agents or may have affected the interpretation of the results or rendered the patient at high risk from treatment complications.

18. Concurrent participation in another therapeutic clinical study.

Related Conditions & MeSH terms

• Bladder Cancer
• Carcinoma, Transitional Cell
• Urinary Bladder Neoplasms

Intervention

Drug:
• Tislelizumab 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.
• RP2D 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.

Locations

Country	Name	City	State
China	Hunan Cancer Hospital	Changsha	Hunan
China	Xiangya Hospital, Central South University	Changsha	Hunan
China	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong
China	Sun Yat-sen Memorial Hospital	Guangzhou	Guangdong
China	The First Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong
China	The Third Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong
China	Zhujiang Hospital of Southern Medical University	Guangzhou	Guangdong
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker Endpoint Analyses	To explore biomarkers in urine, blood, and tumor tissues (collected from TURBT) at baseline and tissue samples collected from radical cystectomy and their association with patient prognosis, clinical efficacy, and drug resistance. Biomarkers include PD-L1, Ki67 expression in tumor tissues, immune cells profiling and gene expression and tumor mutation profiling.	24 months
Primary	Phase I: the safety dose of the combination of Tislelizumab and palbociclib	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.; In this study, Dose-limiting toxicity (DLT) was defined as drug-related adverse reactions (according to the NCI CTC 5.0 grading criteria) after treatment: = Grade II liver and kidney injury, grade III other non-hematological toxicity, and grade IV hematological toxicity.	12 months
Primary	Phase II: Pathological complete response rate(pCR)	pathological complete response rate (pCR rate), the measure to determine whether complete response (pT0N0) is achieved based on pathological findings of surgical tissue samples.	24 months
Secondary	Pathological Downstaging(pDS)	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 rat	24 months
Secondary	Event-free survival (EFS)	Event-free survival (EFS) is defined as the time from the start of first dose of neoadjuvant treatment to disease progression, death from any cause, or onset of other tumors.	24 months
Secondary	overall survival (OS)	OS defined as the time from the date the participant started study drug to death for any reason.	24 months
Secondary	Safety and AE	During safety analysis, extent of exposure to investigational agents (including duration of exposure and dosage)and AEs will be summarized. Description of AEs will be mapped to the Medical Dictionary for Regulatory Activities (MedDRA) terms and graded per NCI-CTCAE v5.0. All TEAEs will be summarized. A treatment-emergent adverse event (TEAE) is defined as an AE that had a worsening in severity from baseline (pretreatment) on or after the first dose of investigational agent(s) and up to 30 days after investigational agent(s) discontinuation or initiation of a new anticancer therapy. Postoperative complications (surgery-related AE) will be graded according to the Clavien-Dindo classification.	24 months