CHemotherapy And Sequential ImmunoTherapy for locally advanced urothelial cancer: the CHASIT study

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 58

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 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

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 Gue*rin 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: 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). 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 stud

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The pathological complete response rate (pCR), defined as the proportion of<br /><br>patients without residual urothelial cancer in the surgical resection specimen,<br /><br>stage ypT0N0/ypTisN0.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Progression-free, cancer-specific and overall survival at 24 months.</p><br>

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