This study has been transitioned to CTIS with ID 2024-512211-41-00 check the CTIS register for the current data. In this study, we investigate whether induction with immunotherapy, followed by chemoradiation as consolidative therapy is an effective…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy defined as bladder-intact event-free survival (BI-EFS)
Primary endpoint readout will be BI-EFS. Events are defined as death by any
cause, muscle-invasive recurrence in the bladder or in the ureter, distal of
the crossing with the common iliac artery, nodal or distant recurrencee,
cystectomy, or switch to cisplatin-based chemotherapy.
BI-EFS will be determined starting from the initiation of the study drug by
CT-imaging, mpMRI of the bladder and cystoscopy. At the time of analysis,
patients without an event will be censored at the time point of their last CT,
mpMRI of the bladder or cystoscopy assessment.
Secondary outcome
Efficacy : other efficacy endpoints such as
- Recurrence-free survival (RFS), defined as time from start of therapy until
the following events: muscle-invasive recurrence in the bladder
or in the ureter, distal of the crossing with the common iliac artery, nodal or
distant recurrence, switch to cisplatin-based chemotherapy or death by any
cause. A decision to switch to cystectomy is not an event, as RFS is meant to
provide a measurement of induction therapy efficacy.
- Overall survival (OS), defined as the time between the date of enrollment and
the date of death. For subjects without documentation of death, OS will be
censored on the last date the subject was known to be alive.
- The rate of NMIBC recurrence-free survival (RFS), overall survival (OS), and
the rate of NMIBC will be established.
Safety
- Feasibility to proceed to CRT: assessed by CT-scanning and mpMRI of the
bladder after finalizing treatment with checkpoint inhibition, combined with
clinical evaluation by the treating physician. When there is no progressive
disease detected on imaging and there are no medical contraindications to
proceed with CRT, we consider CRT feasibile.
- Safety of CRT
- Safety of ipi/nivo
- Safety of CRT as consolidative therapy after induction ipi/nivo
All grade AEs both treatment- and non-treatment related will be provided as
measured according to CTCAE 5.0.
Diagnostic value of mpMRI of the bladder
Tumor evaluation by AI based radiological assessment of pre- and on-treatment
mpMRI will be established to identify nonresponding patients
Translational
Biomarkers - PD-L1, TMB, molecular subtypes, predictive value of ctDNA (in
urine and plasma) and imaging biomarkers (AI) will be assessed for correlation
with outcome (recurrence and OS)
Subjective measures
QoL and bladder function
Background summary
Although muscle-invasive urothelial bladder cancer can be cured by surgery,
recurrence rates are high. To improve outcome, patients can be treated with
neo-adjuvant cisplatin-based chemotherapy. However, cystectomy is a procedure
with a high risk of morbidity and even mortality. Loss of the bladder has a
major impact on a patient*s quality of life (QoL). Concurrent chemoradiotherapy
is recognized as an alternative to cystectomy in selected patients .
Immunotherapy is developed to encourage the immune system to attack tumor
cells. Ipilumumab and nivolumab are examples of immunotherapy.
In a previous study, twenty-four patients with urothelial bladder cancer were
treated with ipilumumab and nivolumab. In this study, all patients could
undergo surgery after pre-treatment with immunotherapy. In 23 out of 24
patients, surgery was performed within 12 weeks. In one patient, surgery had a
delay of one month due to adverse events. After treatment with ipilimumab and
nivolumab, a reduction of the tumor size (or even no remaining disease) was
observed in 19 out of 24 patients.
Based on promising results of immunotherapy, we here propose to study induction
ipilimumab + nivolumab, followed by bladder-sparing consolidative therapy using
MMC in combination with fluoropyrimidines + radiotherapy to the bladder. By
this sequential approach, we aim to reduce the risk of recurrence. In case this
treatment schedule appears to be effective, this may lead to less cystectomies
in urothelial bladder cancer patients.
Study objective
This study has been transitioned to CTIS with ID 2024-512211-41-00 check the CTIS register for the current data.
In this study, we investigate whether induction with immunotherapy, followed by
chemoradiation as consolidative therapy is an effective bladder-sparing
therapy.
Study design
Patients will be treated with immunotherapy in three cycles:
- Day 1: ipilimumab 3 mg/kg
- Day 22: ipilimumab 1 mg/kg + nivolumab 3 mg/kg
- Day 43: nivolumab 3 mg/kg
After induction therapy, the first response evaluation will be performed by
cystoscopy, CT- and mpMRI of the bladder. When there is no progressive disease,
patients will proceed to chemoradiotherapy (CRT). This is a standard approach
in which radiation is executed regarding the local protocol. Probably, this
will be 4-5 consecutive weeks from monday-friday.
The schedule for chemotherapy is as follows:
- A single dose of mitomycin C on day 1 of the radiation period
- Either 5-FU intraveniously for 5 days in week 1 and 4 of the radiation
period, or capecitabin tablets during the radiation period.
The second response evaluation with an mpMRI in selected centers, cystoscopy,
CT scanning of the thorax and abdomen will take place three months after CRT.
Follow-up takes place 6, 12, 18, 24, 30 en 36 months after completing CRT.
Intervention
Patients will be treated with immunotherapy in three cycles:
- Day 1: ipilimumab 3 mg/kg
- Day 22: ipilimumab 1 mg/kg + nivolumab 3 mg/kg
- Day 43: nivolumab 3 mg/kg
After induction therapy, tumor evaluation will be performed by cystoscopy, CT-
and mpMRI of the bladder. When there is no progressive disease, patients will
proceed to chemoradiotherapy (CRT).
The schedule for chemotherapy is as follows:
- A single dose of mitomycin C on day 1 of the radiation period
- Either 5-FU intraveniously for 5 days in week 1 and 4 of the radiation
period, or capecitabin tablets during the radiation period.
Study burden and risks
Participating in this study requires extra time. Patients need to visit the the
hospital three times to receive immunotherapy. Furthermore, patients are
schedules for additional controls during the study. For response evaluation
after immunotherapy, patients require a cystoscopy, a CT-scan and a mpMRI of
the bladder. The CT-scan and mpMRI can be unpleasant for claustrofobic
patients, A cystoscopy could be painfull afterwards and could result in mild
hematuria.
Several times, blood will be drawn and urine will be collected. Two ECGs will
be performed. We expect patients not to experience these examinations to be
unpleasant.
Women with childbearing potential should have a negative pregnancy test.
By participating in this study, patients could experience immune related
adverse events, which may require treatment with steroids or hospitalization.
It may even be necessary to postpone CRT due to adverse events
Questionnaires regarding QoL and bladder function will be provided several
times during this study, which could be confrontational for some patients. A
subset of patients will be able to join focus groups in order to expand the QoL
research in the study.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
1. Willing and able to provide informed consent
2. Age >= 18 years
3. Patients with cT2-4aN0-2M0 urothelial bladder cancer, seeking an alternative
to radical cystectomy and/or patients who are medically unfit for surgery.
Patients with suspected metastatic disease are not eligible.
4. Lymph nodes should be amenable for inclusion into the radiation field
according to the multidisciplinary tumor board and/or follow-up consultations
between the treating physician and the radiation oncologist.
5. World Health Organization (WHO) performance Status 0 or 1.
6. Urothelial cancer is the dominant histology (>70%). %). A small cell
component is not allowed.
7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks
from diagnostic TUR available.
8. 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 as per Cockcroft-Gault formula, AST <= 2.5 x ULN, ALT <=2.5
x ULN, Bilirubin <=1.5 X ULN
9. Negative pregnancy test (βHCG in urine or blood) for female patients of
childbearing potential within 2 weeks prior to day 1 of start immunotherapy.
10. Highly effective contraception for both male and female subjects if the
risk of conception exists. Female patients of childbearing potential must
comply with contraception methods as requested by the study protocol
Exclusion criteria
1. Previous pelvic irradiation
2. Upper tract urothelial cancer
3. Extensive CIS of the bladder
4. Bilateral hydronephrosis
5. Previous intravenous chemotherapy for bladder cancer
6. Contra-indication to one of the study treatment components, or mpMRI
7. 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
8. Documented history of severe autoimmune disease (e.g. inflammatory bowel
disease, myasthenia gravis)
9. Prior CTLA-4 or PD-(L)1 -targeting immunotherapy
10. Known history of Human Immunodeficiency Virus, active tuberculosis, or
other active infection requiring therapy at the time of inclusion
11. Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic
acid (RNA)
12. Underlying medical conditions that, in the investigator's opinion, will
make the administration of study drug hazardous or obscure the interpretation
of adverse events
13. Medical condition requiring the use of immunosuppressive medications, with
the exceptions of intranasal and inhaled corticosteroids or systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. Steroids as premedication for
hypersensitivity reactions (e.g., CT scan premedication) will be allowed
14. Use of other investigational drugs four weeks or five half lifes before
study drug administration
15. Malignancy, other than urothelial cancer, in the previous 2 years, with a
high chance of recurrence (estimated >10%). Patients with low risk prostate
cancer (defined as Stage T1/T2a, Gleason score <= 6, and PSA <= 10 ng/mL) who are
treatment-naive and undergoing active surveillance are eligible
16. Pregnant and lactating female patients
17. Major pelvic 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
18. Severe infections within 2 weeks prior to enrolment in the study including
but not limited to hospitalization for complications of infection, bacteremia,
or severe pneumonia
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 | CTIS2024-512211-41-00 |
| EudraCT | EUCTR2021-004420-15-NL |
| ClinicalTrials.gov | NCT05200988 |
| CCMO | NL78855.031.21 |