Safety and Efficacy of Camrelizumab for High-risk NMIBC Failing BCG Treatment

Immunotherapy Clinical Trial

Official title:

A Phase I/II Single Arm Study of Intravesical Administration With Camrelizumab for High-risk Non-muscle Invasive Bladder Cancer(NMIBC) Failing in BCG Treatment

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04706598
• Other study ID #: MA-UC-II-004
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 9, 2021
• Est. completion date: December 2024

Study information

• Verified date: December 2023
• Source: Fudan University
• Contact: Dingwei Ye, MD
• Phone: +86-64175590-82800
• Email: dwyeli[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety and efficacy of bladder intravesical Camrelizumab in patients with high-risk non-muscle-invasive bladder cancer who failed BCG therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: December 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years.

2. Histologically-confirmed diagnosis of high risk non-muscle-invasive urothelial cell carcinoma of the bladder (mixed histology tumors allowed if urothelial carcinoma histology is >50%).

3. Fully resected disease at study entry (residual CIS acceptable).

4. BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy(at least five times a week during the induction phase and at least two times a week during the maintenance phase).

5. Ineligible for radical cystectomy or refusal of radical cystectomy.

6. Consent to tissue specimen retrieval and testing.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. Adequate normal organ and marrow function as defined below:

1. Haemoglobin (HB) = 90 g/L

2. Absolute neutrophil count (ANC) =1.5×10^9/L(no granulocyte colony-stimulating factor support for 2 weeks before day 1 of cycle 1)

3. Lymphocyte count=0.500×10^9/L

4. Platelet count =100×10^9/L(No blood transfusions within 2 weeks before day 1 of cycle 1)

5. 4.0×10^9/L=White Blood Cell Count (WBC)=15×10^9/L

6. AST (SGOT)/ALT (SGPT)/Alkaline phosphatase = 2.5 x institutional upper limit of normal(ULN) (excluded Gilbert's disease patients, whose serum bilirubin level = 3x ULN)

7. INR/aPTT=1.5×ULN(Which only applies to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be given a stable dose)

8. Serum creatinine (Cr) = 1.5 times the upper institutional limit of normal (ULN) or Serum creatinine Cl>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)

9. Women of childbearing potential who have a negative serum pregnancy test within 72 hours prior to the first dose should consent to and must use effective contraception during and for 6 months after the end of the study.

10. Men should consent to patients who must use contraception during the study and for 6 months after the end of the study period.

11. The subject is personally willing and able to provide written informed consent to be able to comply with the protocol.

Exclusion Criteria:

1. Muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma.

2. Concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis)urothelial cell carcinoma.

3. Have participated in a clinical trial of an investigational drug or device within 4 weeks prior to receiving the first treatment in this project.

4. Received chemotherapy, targeted small molecule therapy, immunotherapy or radiation therapy following a recent cystoscopy or transurethral resection of a bladder tumour.

5. History of other malignancies within the last 5 years.

6. Active autoimmune disease that has required systemic treatment in the past 2 years.

7. History of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, histoplasmosis (i.e. occlusive bronchiolitis, cryptogenic histoplasmosis), or evidence of active pneumonia on chest CT scan (history of fibrosis in radiation pneumonia), patients with active tuberculosis.

8. Active infection requiring systemic therapy,therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (patients receiving prophylactic antibiotics (e.g. for the prevention of urinary tract infections or chronic obstructive pulmonary disease) can be enrolled).

9. Patients who are pregnant or breastfeeding, or expecting to conceive .

10. Previous treatment with anti-PD-1 monoclonal antibody, PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody, or other drugs that act on T-cell co-stimulation or any other antibody of the checkpoint pathway.

11. Patients with known positive test for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).

12. Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (Hepatitis B reference: HBsAg positive and HBV DNA = 500 IU/ml; Hepatitis C reference: HCV antibody positive and HCV viral copy number > upper limit of normal value).

13. Received a live virus vaccine within 30 days of planned start of study treatment.

14. Has had an allogeneic tissue/solid organ transplant.

15. Long-term oral steroids, more than 10 mg/day of methandrostenolone or similar, must be stopped for 28 days before entry into the group.

16. Evidence of apparently uncontrolled concomitant disease that may affect compliance with the protocol or interpretation of the results, including significant liver disease (e.g. cirrhosis, uncontrolled major seizures or superior vena cava syndrome).

17. Significant cardiovascular disease, such as New York Heart Association heart attack (class II or higher), myocardial infarction, unstable arrhythmia or unstable angina within 3 months prior to study entry.

18. Patients who have had major surgery within 4 weeks prior to study entry, or who are expected to require major surgery during the course of the study, except diagnostic procedures such as TURBT or biopsy.

19. History of autoimmune diseases, including but not limited to severe muscle weakness, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, angio-thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, dry syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

20. History of severe allergy, sensitisation or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins.

21. Patients who, in the opinion of the investigator, are otherwise unable to participate in this trial.

Related Conditions & MeSH terms

• Immunotherapy
• Urinary Bladder Neoplasms

Intervention

Drug:
• Camrelizumab
Solution for Infusion (Intravesical)

Locations

Country	Name	City	State
China	Fudan University Shanghai Cancer Center	Shanghai	Shanghai
China	Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai
China	Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai
China	Shanghai Tenth People's Hospital,Shanghai Tong Ji University School of Medicine	Shanghai	Shanghai

Sponsors (2)

Lead Sponsor	Collaborator
Fudan University	Shanghai Shen Kang Hospital Development Center

Country where clinical trial is conducted

China, 

References & Publications (17)

Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BWG, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016 — View Citation

Catalona WJ, Hudson MA, Gillen DP, Andriole GL, Ratliff TL. Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol. 1987 Feb;137(2):220-4. doi: 10.1016/s0022-5347(17)43959-0. — View Citation

Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP, Lotan Y, Meeks JJ, Michalski JM, Morgan TM, Quale DZ, Rosenberg JE, Zietman AL, Holzbeierlein JM. Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer: American Urological Association/Amer — View Citation

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Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guerin. Urol Oncol. 2013 Nov;31(8):1635-42. doi: 10.1016/j.urolonc.2012.04.010. Epub 2012 — View Citation

He YT, Li DJ, Liang D, Zheng RS, Zhang SW, Zeng HM, Chen WQ, He J. [Incidence and mortality of bladder cancer in China, 2014]. Zhonghua Zhong Liu Za Zhi. 2018 Sep 23;40(9):647-652. doi: 10.3760/cma.j.issn.0253-3766.2018.09.002. Chinese. — View Citation

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Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, Fradet Y, Lacombe L, Kwon ED. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007 Apr 15;109 — View Citation

Kamat AM, Flaig TW, Grossman HB, Konety B, Lamm D, O'Donnell MA, Uchio E, Efstathiou JA, Taylor JA 3rd. Expert consensus document: Consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancer. — View Citation

Mitropoulos DN. Novel insights into the mechanism of action of intravesical immunomodulators. In Vivo. 2005 May-Jun;19(3):611-21. — View Citation

Oddens JR, Sylvester RJ, Brausi MA, Kirkels WJ, van de Beek C, van Andel G, de Reijke TM, Prescott S, Witjes JA, Oosterlinck W. The effect of age on the efficacy of maintenance bacillus Calmette-Guerin relative to maintenance epirubicin in patients with s — View Citation

Pietzak EJ, Bagrodia A, Cha EK, Drill EN, Iyer G, Isharwal S, Ostrovnaya I, Baez P, Li Q, Berger MF, Zehir A, Schultz N, Rosenberg JE, Bajorin DF, Dalbagni G, Al-Ahmadie H, Solit DB, Bochner BH. Next-generation Sequencing of Nonmuscle Invasive Bladder Can — View Citation

Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015 Apr 3;348(6230):69-74. doi: 10.1126/science.aaa4971. — View Citation

Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials — View Citation

Taniguchi K, Koga S, Nishikido M, Yamashita S, Sakuragi T, Kanetake H, Saito Y. Systemic immune response after intravesical instillation of bacille Calmette-Guerin (BCG) for superficial bladder cancer. Clin Exp Immunol. 1999 Jan;115(1):131-5. doi: 10.1046 — View Citation

Witjes JA, Palou J, Soloway M, Lamm D, Kamat AM, Brausi M, Persad R, Buckley R, Colombel M, Bohle A. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of baci — View Citation

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* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The maximum dose of Camrelizumab for intravesical treatment	The maximum tolerated dose (MTD) of Camrelizumab that will be given intravesically to patients with BCG-refractory NMIBC(de-escalated doses of 200/150/100mg) and recommended for phase II studies (RP2D).	3 months after trial initiation(Phase I)
Primary	Event-Free Survival (EFS)	Recurrence of high-grade cancer (TaHG, T1HG, CIS), or disease progression to stage T2 or beyond or lymph node metastasis or distant metastasis, or the need for other treatment (including systemic chemotherapy, radical cystectomy, radiation therapy), and death from any cause.	3 months after patient treatment (Phase II)
Secondary	Incidence of adverse events	Incidence of adverse events and treatment-related adverse events	Until progressive disease or death
Secondary	Assessment of HGRF	High grade cancer recurrence free rate (HGFR) at 6 months and 1 year of treatment.	6 months and 1 year after patient enrollment
Secondary	Assessment of RFS	Recurrence free survival (RFS) at 6 months and 1 year of treatment.	6 months and 1 year after patient enrollment
Secondary	Assessment of PFS	Progression free survival (PFS) at 6 months and 1 year of treatment.	6 months and 1 year after patient enrollment
Secondary	the predictive value of PD-1 expresssion	the predictive value of PD-L1 expression assessed in tumor tissue and urine sample obtained before and after Camrelizumab instillation.	1 year after patient enrollment