We will assess feasibility of pre-operative nivolumab in PD-L1 positive resectable stage II-III urothelial cancer patients
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 primary endpoint is feasibility, defined as the number of patients
undergoing cystectomy within 12 weeks after start of the study drug.
Secondary outcome
1. Efficacy: Efficacy will be defined as the percentage of pathological
complete response (pCR), defined as pT0N0 or pTisN0, at cystectomy. Other
efficacy endpoints will include RFS and OS.
2. Safety: We will provide the frequency of treatment-related toxicities as
measured according to CTCAE 5.0.
3. Translational: Effects of immunotherapy on the UC tumor microenvironment
Background summary
Although muscle-invasive urothelial cancer can be cured by surgery, recurrence
rates are high. To improve outcome, patients are treated with neo-adjuvant
cisplatin-based chemotherapy, which has a high rate of response. Despite
impressive responses, the absolute benefit in terms of overall survival is
marginal. Furthermore, cisplatin-based chemotherapy is contra-indicated in a
significant number of patients due to comorbidity.
Previous studies with neo-adjuvant ipilimumab and nivolumab have shown tumor
regression in the majority of patients with UC.
The effect of immune checkpoint blockade is known to be superior in tumor with
high expression of PD-L1. In this trial, we'll investigate feasibility and
efficacy of pre-operative nivolumab in patient with high PD-L1 expression.
Study objective
We will assess feasibility of pre-operative nivolumab in PD-L1 positive
resectable stage II-III urothelial cancer patients
Study design
This is a phase 1b safety, feasibility and proof-of-principle study of
pre-operative immune checkpoint inhibition in patients with stage II and III
urothelial cancer (cT2-4aN0M0 or T1-4aN1-3M0). This study can be
adapted/expanded into a phase 2 study based on results obtained in this initial
feasibility portion.
Intervention
PD-L1 positive patients (CPS>10%): 3x nivolumab 240 mg, D1, 22 and 43
Study burden and risks
Participation in this triall will be time consuming. Patients will visit the
hospital for three times to receive immune therapy intravenously. Furthermore,
there are some additional checks after surgery.
When treatment with the study drugs is accomplished, a CT-scan and an optional
MRI will be performed to evaluate the response to treatment. Patients who
suffer from claustrofobia can experience these investigations as being
aggravating.
Before the start of treatment, an ECG will be performed. During this trial,
multiple blood examinations will be performed. The burden of these
investigations is considered acceptable.
By participating in this study, patients could experience immune related
adverse events, which may require treatment with steroids or hospitalization.
In case of severe immune related adverse events, surgery may be postponed for
safety reasons.
By participating in this study, surgery is scheduled some weeks later compared
to patients who do not receive pre-operative therapy. A potential disadvantage
is that disease progresses while awaiting surgery. This could lead to a more
difficult surgery with an increased risk for complications or disease relapse.
In the worst case, surgery may not be appropriate anymore.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
1. Resectable muscle-invasive UC (upper urinary tract allowed), defined as: -
cT2-4aN0M0 OR - cT1-4aN1-3M0 2. World Health Organization (WHO) performance
Status 0 or 1. 3. Urothelial cancer is the dominant histology (>70%). 4. PD-L1
status must be determined using the 22C3 pharmDx test. Combined positivity
score (CPS) must be >10 under amendment V3. 5. Screening laboratory values must
meet the following criteria: WBC >= 2.0x109/L, Neutrophils >=1.0x109/L, Platelets
>=100 x109/L, Hemoglobin >=5.5 mmol/L, GFR>30 ml/min, AST <= 1.5 x ULN, ALT <=1.5 x
ULN, Bilirubin <=1.5 X ULN 6. Negative pregnancy test 7. Age >= 18 years
Exclusion criteria
1. Subjects with active autoimmune disease in the past 2 years. Patients with
diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism,
vitiligo, psoriasis or other mild skin disease can still be included.
2. Documented history of severe autoimmune disease (e.g. inflammatory bowel
disease, myasthenia gravis).
3. Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
4. Known history of Human Immunodeficiency Virus infection, or tuberculosis, or
other active infection requiring therapy at the time of inclusion.
5. Positive tests for Hepatitis B or Hepatitis C
6. Underlying medical conditions that, in the investigator's opinion, will make
the administration of study drug hazardous or obscure the interpretation of
adverse events
7. Medical condition requiring the use of immunosuppressive medications
8. Use of other investigational drugs before study drug administration
9. Malignancy, other than urothelial cancer, in the previous 2 years, with a
high chance of recurrence (estimated >10%).
10. Pregnant and lactating female patients.
11. Major surgical procedure within 4 weeks prior to enrolment or anticipation
of need for a major surgical procedure during the course of the study other
than for diagnosis.
12. Severe infections within 2 weeks prior to enrolment in the study
13. Significant cardiovascular disease, such as New York Heart Association
cardiac disease (Class II or greater), myocardial infarction within 3 months
prior to enrolment, unstable arrhythmias and unstable angina.
14. Previous intravenous chemotherapy for bladder cancer. Prior low-dose
sensitizing chemotherapy used for combined modality treatment, or radiation
alone, is allowed if patients have recurred after an initial response. Patients
with residual disease after (chemo)radiation for bladder cancer are not
eligible.
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 |
|---|---|
| EudraCT | EUCTR2021-002033-41-NL |
| ClinicalTrials.gov | NCT04871594 |
| CCMO | NL77423.031.21 |