Chemotherapy and Sequential Immunotherapy for Locally Advanced Urothelial Cancer (CHASIT)

Chemotherapy and Sequential Immunotherapy for Locally Advanced Urothelial Cancer: the CHASIT Study

Patients with locally advanced or clinically node positive urothelial carcinoma treated with chemotherapy, will receive 3 cycles of avelumab, followed by radical surgery.

Study Overview

• Status: Recruiting
• Conditions: Urothelial Carcinoma
• Intervention / Treatment: Drug: Avelumab

Detailed Description

Patients with locally advanced or clinically node positive urothelial carcinoma of the bladder, ureter or urethra (cT4NxM0 or cTxN1-N3M0) with at least stable disease after treatment with 3-4 cycles of platinum-based chemotherapy, will be treated with 3 cycles of avelumab (anti-PD-L1). If there are no signs of disease progression after avelumab treatment, radical surgery of the primary tumor and a pelvic lymph node dissection will follow.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: J L Boormans, MD PhD; Phone Number: 0031 10 7032612; Email: j.boormans@erasmusmc.nl
• Study Contact Backup: Name: V C Rutten, MD; Email: v.rutten@erasmusmc.nl

Study Locations

• Netherlands
  • Brabant
    • Breda, Brabant, Netherlands, 4818 CK
      • Recruiting
      • Amphia Ziekenhuis
      • Contact: Westgeest
      • Principal Investigator: Leijte
      • Principal Investigator: Westgeest
    • Den Bosch, Brabant, Netherlands, 5223 GZ
      • Recruiting
      • Jeroen Bosch Ziekenhuis
      • Contact: Smilde
      • Principal Investigator: Smilde
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GD
      • Recruiting
      • Radboud UMC
      • Contact: Mehra
      • Principal Investigator: vd Heijden
      • Principal Investigator: Mehra
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 GD
      • Recruiting
      • Erasmus MC
      • Contact: Boormans; Email: chasit@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years.
2. Have histologically confirmed urothelial carcinoma of the bladder, upper urinary tract or urethra; a maximum of 50% of aberrant histology is allowed.
3. Have clinical stage cT4NxM0 or cTxN1-N3M0 as assessed by bimanual examination under anaesthesia, CT scan, MRI scan or PET-CT scan.
4. Have at least stable disease after a minimum of 3 or a maximum of 4 cycles of induction chemotherapy with cisplatin / carboplatin + gemcitabine according to RECIST v1.1.
5. Are fit and willing to undergo radical surgery with removal of lymph node template including all affected lymph nodes and the primary tumor.
6. World Health Organisation performance status of 0-2.
7. Provide written informed consent.
8. Negative pregnancy test in women with childbearing potential.

9. Adequate bone marrow function, including:

   1. Absolute neutrophil count (ANC) ≥1,500/mm3 or 1.5 x 109/L;
   2. Platelets ≥100 x 109/L;
   3. Hemoglobin ≥5.6 mmol/L (may have been transfused).
10. Adequate renal function, defined as estimated creatinine clearance ≥30 mL/min as calculated by the CKD-EPI eGFR.

11. Adequate liver function, including:

    1. Total serum bilirubin <1.5 x upper limit of normal (ULN);
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x ULN.

Exclusion Criteria:

1. Predominant (>50%) non-urothelial carcinoma histology in the diagnostic endoresection specimen of the bladder, urethra or upper urinary tract.
2. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection.
3. Have an estimated creatinin clearance as assessed by the CKD-EPI eGFR of <30 ml/min.
4. Prior exposure to immune-mediated therapy with exclusion of Bacillus-Calmette Guérin intravesical instillations, including but not limited to other anti-CTLA-4, anti PD-1, anti PD-L1, or anti-PD-L2 antibodies.
5. Persisting toxicity related to prior chemotherapy (Grade >2 NCI CTCAE v5.0).
6. A diagnosis of any other malignancy within 2 years prior to inclusion, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the breast or of the cervix, low grade prostate cancer on surveillance without any plans for treatment intervention, or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease.
7. ≤2 cycles of induction platinum-based chemotherapy received.
8. Progression of disease during or following induction platinum-based chemotherapy, as assessed by RECIST v1.1.
9. Distant metastatic disease.
10. Previous pelvic radiation therapy.
11. Breastfeeding women.
12. Bilateral upper urinary tract urothelial carcinoma.
13. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
14. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
15. Active infection requiring systemic therapy.
16. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
17. Known prior or suspected hypersensitivity to avelumab.

18. Current use of immunosuppressive medication, EXCEPT the following:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
    2. Systemic corticosteroids at (equivalent) doses of maximum 10 mg prednisone;
    3. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
19. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
20. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivate vaccines (for example, inactivated influenza vaccines) or mRNA vaccines (for example, COVID-19 vaccines).
21. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, and pneumonitis; psychiatric condition including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Avelumab; 3 cycles of avelumab (Bavencio), 800mg intravenous instillation in 60 min, every 2 weeks.	Drug: Avelumab; 3 cycles of avelumab (800mg, every 2 weeks); Other Names: Bavencio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate	the proportion of patients without residual UC in the surgical resection specimen, ypT0N0 (carcinoma situ is allowed), in the intention-to-treat analysis.	About 1 month after radical surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Progression-free, cancer-specific and overall survival at 24 months, calculated from the time of 1st administration of avelumab	24 months after radical surgery
Non-invasive urothelial cancer	The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0	About 1 month after radical surgery
Delay in surgery	The proportion of patients in whom radical surgery is delayed >8 weeks after last administration of avelumab due to toxicity.	About 1 month after radical surgery
Adverse events	Adverse events of assessed by the CTCAE v5.0	90 days after administration of the last cycle of avelumab
Surgical complications	Assesed by Clavien-Dindo classification within 30 and 90 days from date of surgery	90 days after radical surgery

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Principal Investigator: J L Boormans, MD PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2022
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 26, 2022
• First Submitted That Met QC Criteria: October 26, 2022
• First Posted (Actual): October 31, 2022

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Safety; Immunotherapy; Chemotherapy; Pathological response
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Transitional Cell; Antineoplastic Agents; Antineoplastic Agents, Immunological; Avelumab
• Other Study ID Numbers: NL80678.078.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No