This study has been transitioned to CTIS with ID 2024-516940-24-00 check the CTIS register for the current data. To demonstrate the benefit of sequential chemo-immunotherapy in increasing the proportion of patients reaching a pathological complete…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The pathological complete response rate (pCR), defined as the proportion of
patients without residual urothelial cancer in the surgical resection specimen,
stage ypT0N0/ypTisN0.
Secondary outcome
Progression-free, cancer-specific and overall survival at 24 months.
Background summary
The global incidence of urothelial cancer (UC) is >=300.000 patients/yr and
accounts for 165.000 deaths/yr. Patients with locally advanced irresectable,
stage cT4bNxM0 or clinically node-positive, stage cTxN1-N3M0, disease have a
very poor outcome. However, in selected cases cure is still possible provided
that: i) patients experience an adequate response to induction chemotherapy and
ii) thereafter, undergo surgery with radical removal of the primary tumor and
all locoregional lymph nodes. Nevertheless, the chances of long-term survival
in these patients strongly depends on pathology of the resection specimen; a
minority of patients (15%) experience a complete pathological response (pCR),
meaning absence of residual cancer. Patients who experience a pCR have a 5-year
overall survival of 70-80%. Conversely, patients who have residual invasive
disease, stage >=ypT2N0, or nodal metastases, stage >ypN0, after induction
chemotherapy have a 5-yr overall survival of only 20%. So, there is a clear
unmet need to improve the pCR rate and thereby the survival of patients with
locally advanced irresectable, stage cT4bNxM0, or clinically node-positive,
stage cTxN1-3M0, UC of the bladder or upper urinary tract. To address this
need, we propose to conduct a study with induction chemotherapy, which is, in
the absence of disease progression, followed by immunotherapy. Thereafter,
patients undergo radical surgery with removal of the affected organ and
locoregional lymph nodes.
Study objective
This study has been transitioned to CTIS with ID 2024-516940-24-00 check the CTIS register for the current data.
To demonstrate the benefit of sequential chemo-immunotherapy in increasing the
proportion 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.
Study design
A multicenter prospective phase II non-randomized intervention study.
Intervention
All subjects receive three courses of anti-PD-1 immunotherapy with avelumab at
a concentration of 800mg q2w, which is followed by radical surgery with removal
of lymph nodes and the primary tumor.
Study burden and risks
Subjects receive three cycles of avelumab 800 mg q2w, which is followed by
radical surgery with lymph node dissection within 4 to 8 weeks after day 14 of
the last cycle of avelumab. Subjects are asked to provide consent for the
collection of additional blood and urine samples; a maximum of 14 in two years*
time. Collection of additional blood and urine samples is scheduled during
blood draw for routine clinical care. In case of disease progression during the
study period, subjects must undergo a biopsy of a suspected metastatic site for
confirmatory diagnostic purposes and consent is asked to collect one additional
sample for research purposes. It is expected that sequential
chemo-immunotherapy is more effective, in terms of pCR rate, than monotherapy
with chemotherapy, which is the current standard of care in patients with
locally advanced irresectable, stage cT4bNxM0, or clinically node-positive,
stage cTxN1-N3M0 UC. The hypothesis is that the immune-priming effects of
chemotherapy result in an improved response when sequential immunotherapy is
administered. Moreover, the selection of UC patients without progressive
disease following induction chemotherapy translates in a higher likelihood of
benefit as compared to studies that included all-comers. In addition, the
toxicity profile of immunotherapy is different from that of chemotherapy but in
general it is less toxic with less grade >3 side-effects. Participating
hospitals can offer an additional bladder biopsy after finishing chemotherapy.
This will depend on the availability and capacity of the participating
hospital. Possibilities will be discussed at study initiation or at request of
the participating hospital.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
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 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516940-24-00 |
| EudraCT | EUCTR2022-000514-33-NL |
| CCMO | NL80678.078.22 |