Chasit

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12], Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

29 Oct 2024 → ongoing

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516940-24-00

EudraCT number

2022-000514-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To demonstrate the benefit of sequential chemo-immunotherapy in increasing the number of patients reaching a pathological complete response (pCR) at radical surgery in patients with locally advanced irresectable (stage cT4bNxM0) or clinically node-positive (stage cTxN1-N3M0) UC whose disease did not progress on or following completion of platinum-containing chemotherapy.

Secondary objectives 5

1. The two-year progression-free, cancer-specific and overall survival, defined as the time from 1st administration of avelumab until two years of follow-up are completed or until: death, cancer-specific death, radiological progression as assessed by cross-sectional imaging, or abortion of radical surgery due to perioperative irresectable primary tumor or presence of metastatic disease.
2. Safety and tolerability of preoperative avelumab as assessed by the CTCAE v5.0 (Appendix 9).
3. Clavien-Dindo surgical complications within 30 and 90 days from date of surgery (Appendix 10).
4. The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0.
5. The proportion of patients in whom radical surgery is delayed >8 weeks after day 14 of the last administration of avelumab due to immune-related toxicity.

Conditions and MedDRA coding

locally advanced urothelial cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 cT4bNxM0 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: a. Absolute neutrophil count (ANC) ≥1,500/mm3 or 1.5 x 109/L; b. Platelets ≥100 x 109/L; c. 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: a. Total serum bilirubin <1.5 x upper limit of normal (ULN); b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x ULN.

Exclusion criteria 21

1. Predominant (>50%) non-urothelial carcinoma histology in the diagnostic endoresection specimen of the bladder, urethra or upper urinary tract.
2. Previous pelvic radiation therapy.
3. Breastfeeding women.
4. Bilateral upper urinary tract urothelial carcinoma.
5. 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.
6. 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.
7. Active infection requiring systemic therapy.
8. 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).
9. Known prior or suspected hypersensitivity to avelumab.
10. Current use of immunosuppressive medication, EXCEPT the following: a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection); b. Systemic corticosteroids at (equivalent) doses of maximum 10 mg prednisone; c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
11. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
12. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection.
13. 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).
14. Have an estimated creatinin clearance as assessed by the CKD-EPI eGFR of <30 ml/min.
15. Prior exposure to immune-mediated therapy with exclusion of Bacillus-Calmette Guérin intravesical instillations, including but not limited to other anti-CTLA-4, anti PD1, anti PD-L1, or anti-PD-L2 antibodies.
16. Persisting toxicity related to prior chemotherapy (Grade >2 NCI CTCAE v5.0).
17. 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.
18. ≤2 cycles of induction platinum-based chemotherapy received.
19. Progression of disease during or following induction platinum-based chemotherapy, as assessed by RECIST v1.1.
20. Distant metastatic disease.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathological complete response rate, defined as the proportion of patients without residual UC in the surgical resection specimen, ypT0N0 (carcinoma situ is allowed), in the intention-to-treat analysis.

Secondary endpoints 5

1. Progression-free, cancer-specific and overall survival at 24 months, calculated from the time of 1st administration of avelumab.
2. Safety and tolerability of preoperative avelumab as assessed by the CTCAE v5.0 (Appendix 9).
3. Clavien-Dindo surgical complications (within 30 and 90 days from date of surgery) (Appendix 10).
4. The rate of non-invasive urothelial cancer in the surgical resection specimen, stage ypT0N0/ypTisN0/ypTaN0/ypT1N0.
5. The proportion of patients in whom radical surgery is delayed >8 weeks after last administration of avelumab due to toxicity.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Sponsor organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Prof. dr. J.L. Boormans

Public contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Prof. dr. J.L. Boormans

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications