This study has been transitioned to CTIS with ID 2022-500630-29-00 check the CTIS register for the current data. We hypothesise that treatment with nivolumab will extend disease-free survival, compared with placebo, as adjuvant therapy in all…
ID
Source
Brief title
Condition
- Bladder and bladder neck disorders (excl calculi)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the disease free survival (DFS) for nivolumab versus placebo in
Subjects with tumours expressing PD-L1 (>1% membranous staining in tumour
cells) and All randomized subjects
Secondary outcome
• To compare non-urothelial tract recurrence free survival (NUTRFS) for
nivolumab versus placebo in subjects with tumours expressing PD-L1 (>1%
membranous staining in tumour cells) and all randomized subjects
• To compare the disease specific survival (DSS) for nivolumab and placebo in
subjects with tumours expressing PD-L1 (>1% membranous staining in tumour
cells) and all randomized subjects
• To compare the overall survival (OS) for nivolumab versus placebo in subjects
with tumours expressing PD-L1 (>1% membranous staining in tumour cells) and all
randomized subjects.
Background summary
CA209-274 is a phase 3 randomized, double-blind, placebo controlled study of
adjuvant nivolumab in subjects who have undergone radical resection of invasive
urothelial carcinoma (IUC) originating in the bladder or upper urinary tract
(renal pelvis or ureter) and are at high risk of recurrence.
Subjects may have received neo-adjuvant cisplatin based chemotherapy; subjects
who underwent radical resection without neo-adjuvant cisplatin chemotherapy
must be ineligible for or refusing adjuvant cisplatin based chemotherapy.
Patients with invasive disease at radical resection of IUC are at high risk of
recurrence and are in need additional treatment options. Most urothelial
tumours originate in the urinary bladder (90%) or upper urinary tract (~9-10%
in renal pelvis/ureter). Invasive tumours in the upper urinary tract are
typically managed with radical resection alone (radical nephroureterectomy
[RNU] or radical ureterectomy [RU]).
Standard of care treatment for muscle invasive bladder cancer (MIBC) is
cisplatin based neo-adjuvant chemotherapy followed by radical cystectomy.
Patients who have invasive residual disease at radical resection and have not
received neo-adjuvant cisplatin may go on to receive adjuvant cisplatin based
chemotherapy which, despite not having shown definitive clinical benefit, is
used in 20% of patients undergoing radical cystectomy in the US. Up to 60% of
patients who undergo radical cystectomy are not candidates for adjuvant
cisplatin based chemotherapy because they received neoadjuvant chemotherapy or
they are cisplatin ineligible.
This population has a significant unmet need as there are no treatment options
available to help reduce the risk of recurrence and improve survival. The
checkpoint inhibition approach is attractive in this setting considering the
lack of effective, available treatment options and the positive preliminary
results with PD-1/PD-L1 blockade in advanced bladder cancer.
Study objective
This study has been transitioned to CTIS with ID 2022-500630-29-00 check the CTIS register for the current data.
We hypothesise that treatment with nivolumab will extend disease-free survival,
compared with placebo, as adjuvant therapy in all randomized patients and in
patients with PD-L1 expressing tumours (membranous staining in > 1%) who are at
high risk of recurrence after undergoing radical resection of invasive
urothelial carcinoma (IUC).
Study design
Approximately 700 subjects will be randomized in a blinded fashion 1:1 to
nivolumab versus placebo within 120 days of radical resection and stratified by
nodal status (N+ vs. N0/x with < 10 nodes removed vs. N0 with < 10 nodes
removed), tumour PD-L1 expression (>1%, < 1%/ indeterminate), and use of
cisplatin neo-adjuvant chemotherapy.
Treatment, in the absence of prohibitive toxicities, disease
recurrence/progression, or withdrawal of consent will be continued for a
maximum of 1 year. The co-primary endpoint is DFS in subjects with tumours
expressing PD-L1 at >1% (2.5% alpha) and in all randomized subjects (2.5%
alpha).
The overall sample size is set up to allow a clinically meaningful effect to be
statistically significant at alpha level of 2.5% (two-sided) in the all
randomized group. Even weighting of the alpha distribution between DFS
assessment in all randomized (N = 700) and PD-L1 expressers (~ 46% of the all
randomized population) reflects an assumption of enrichment of nivolumab
efficacy in the PD-L1 expressers.
At the time of the original the original study design, the anticipated
prevalence of PD-L1+ was 46% and the PD-L1-ve population in the study was
capped at 54%. During the execution of the study the PD-L1+ rate was
approximately 42%, for this reason in the revised protocol 04 the cap was
removed to make the study sample representative of the study population. Hence,
it is anticipated that the final population will include approximately 42% of
patients who are PD-L1+.
The number of randomised subjects with upper tract urothelial cancer (UTUC;
renal pelvis and ureter cancers) will be capped at approximately 20% (128
subjects) of total global enrolment. Once approximately 128 subjects with UTUC
are randomised, only subjects with bladder cancer will be enrolled.
Following discontinuation of study therapy, subjects will be followed for
survival and those that have not had a non-urothelial tract recurrence will be
followed for recurrence.
Intervention
Nivolumab monotherapy or placebo, administered IV at 240 mg, every 2 weeks
until recurrence, unacceptable toxicity or discontinuation from study for a
maximum of 1 year.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements
including blood tests for safety assessment. Pregnancy testing (for females of
child bearing potential) and monitoring for adverse events.
Subjects will be evaluated for presence or continued lack of tumour until
non-urothelial tract recurrence as below:
• Non-cystoscopy tumour imaging assessments (CT of chest, and CT or MRI of
abdomen, pelvis, upper urinary tract, and all known sites of disease) will
occur;
o Every 12 weeks from the date of first dose to Week 96
o Then every 16 weeks from Week 96 to Week 160
o Then every 24 weeks until non-urothelial tract recurrence or treatment is
discontinued (whichever occurs later) for a maximum of 5 years
• Cystoscopy in subjects with upper GU primaries who still have bladder intact
will occur (in addition to other tumour imaging assessments;
o Every 12 weeks from the date of first dose to Week 48
o Then every 24 weeks from Week 48 to Week 96
o Then every 48 weeks until non-urothelial tract recurrence or treatment is
discontinued (whichever occurs later) for a maximum of 5 years.
Blood will also be collected at certain visits for research purposes (PK,
immunogenicity and biomarker studies). The frequency of visits and number of
procedures carried out during this trial would typically be considered over and
above standard of care. The procedures are carried out by trained medical
professionals and every effort will be made to minimise any risks or discomfort
to the patient. Treatment for cancer often has side effects, including some
that are life threatening.
An independent Data Monitoring Committee (DMC) will be utilised in this trial
to ensure that the safety data is reviewed during the study.
New Immune system targeted therapy (immunotherapies) such as Nivolumab could
potentially provide clinical benefit and improvement in the outcome for
patients with this disease (disease improvement and improvement in survival).
However, with all experimental drugs and clinical trials, there are known and
unknown risks. Study medication and procedure related risks are outlined in the
patient information sheet in detail to ensure the patients are fully informed
before agreeing to take part in the study.
Sanderson Road Unit 2
Uxbridge UB81LZ
GB
Sanderson Road Unit 2
Uxbridge UB81LZ
GB
Listed location countries
Age
Inclusion criteria
1. All subjects must be status post radical surgical resection (R0) for
Invasive Urothelial Carcinoma performed within 120 days prior to
randomization.Subjects with carcinoma in situ in ureteral or urethral margins
are eligible for study entry , 2. All subjects must have pathologic evidence of
urothelial carcinoma (originating in bladder, ureter, or renal pelvis) at high
risk of recurrence based on pathological staging of radical surgery tissue(see
protocol for more details), 3. Dominant component of histology needs to be
urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies
(e.g. minor variants) are accepted, 4. All subjects must have disease-free
status defined as no clinical or radiographic evidence of recurrence of disease
documented by a complete physical examination and imaging studies within 4
weeks of randomization. Subjects with equivocal nodes less than 15 mm in short
axis may be eligible after discussion with BMS medical monitor. All suspect
lesions identified during screening radiographic procedures should be discussed
with the Medical Monitor prior to randomisation.
i)Imaging studies must include CT of chest and CT or MRI of abdomen, pelvis,
and all known sites of resected disease including cystoscopy in subjects with
upper GU primaries who still have bladder intact. Brain imaging (MRI except
where contraindicated in which CT scan is acceptable) must be completed within
4 weeks prior to randomization for subjects with clinical suspicion of CNS
disease.
ii)Subjects who are found to have high risk NMIBC at the time of screening are
not eligible for study entry. Patients with low-risk papillary lesions may
enter the study if rendered free of disease at cystoscopy. Subjects with
intermediate-risk NMIBC may enter the study if intravesical chemotherapy or BCG
is not required. Screening cystoscopy may occur within 60 days of randomisation
and is encouraged to be done prior to other imaging. Any suspect lesions seen
of cystoscopy should be biopsied to rule-out the possibility of high-risk
lesions., Low-risk NMIBC is defined as low-gread lesions or papillary
urothelial neoplasms of low malignant potential (PUNLMP: WHO/ISP 2004 grading
system), or TaG1 lesions (WHO 1973 grading system) that are less than 3cm in
diameter.
High-risk NMIBC is defined as any T1 lesion, and lesion containing carcinoma in
situ (CIS) either alone or concomitantly with papillary disease (e.g. CIS with
Ta/T1 lesions0, and any Ta high-grade (TaHG; WHO/ISUP 2004 grading system) or
TaG3 (WHO 1973 grading system) lesion.
Intermediate-risk NMIBC is defined as lesions not meeting the criteria of
high-risk or low-risk., 5. Tumor tissue from the most recently resected site of
disease (preferable) or from the transurethral resection that, yielded the
initial muscle invasive diagnosis must be provided for biomarker analyses. In
order to be randomized, a subject must have a PD-L1 expression level
classification (>=1%, < 1%, indeterminate) as determined by the central
lab. , 6. Life expectancy >= 6 months, 7. Eastern Cooperative Oncology Group
(ECOG) performance status (PS) 0 or 1. Subjects who have not received cisplatin
based neoadjuvant chemotherapy and are considered ineligible for cisplatin
adjuvant chemotherapy, may enter the study with ECOG PS 2 (see Appendix 2), 8.
Prior surgery that required general anesthesia must be completed at least 4
weeks before study drug administration. Surgery requiring local/epidural
anesthesia must be completed at least 72 hours before study drug
administration. TUR must be completed 14 days before randomisation
Exclusion criteria
1. Partial cystectomy in the setting of bladder cancer primary tumor or partial
nephrectomy in the setting of renal pelvis primary tumor., 2. Adjuvant systemic
or radiation therapy for urothelial or prostatic carcinoma following radical
surgical resection of urothelial carcinoma., 3. Any serious or uncontrolled
medical disorder that, in the opinion of the investigator, may increase the
risk associated with study participation or study drug administration, impair
the ability of the subject to receive protocol therapy, or interfere with the
interpretation of study results., 4. Prior malignancy active within the
previous 3 years except for locally curable cancers that have been apparently
cured, such as basal or squamous cell skin cancer, prostate cancer with
evidence of undetectable Prostate Specific Antigen (PSA) or carcinoma in situ
of the prostate, cervix or breast. Patients with known history of recent
metastatic urothelial carcinoma will be excluded, 5. Subjects with active,
known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring
hormone replacement, psoriasis not requiring systemic treatment, or conditions
not expected to recur in the absence of an external trigger are permitted to
enroll., 6. Subjects with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration.
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune
disease., 7. Subjects with history of life-threatening toxicity related to
prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other
antibody or drug specifically targeting T-cell co-stimulation or immune
checkpoint pathways) except those that are unlikely to re-occur with standard
countermeasures (eg, hormone replacement after adrenal crisis)., 8. All
toxicities attributed to prior anti-cancer therapy other than nephropathy,
neuropathy, hearing loss, alopecia and fatigue must have resolved to Grade 1
(NCI CTCAE version 4) or baseline before administration of study drug. Subjects
with toxicities attributed to prior anti-cancer therapy which are not expected
to resolve and result in long lasting sequelae, such as neuropathy after
platinum based therapy, are permitted to enroll. See protocol inclusion
criterion 2) i) (5) for renal function eligibility. Neuropathy must have
resolved to Grade 2 (NCI CTCAE version 4)., 9. Treatment with any chemotherapy,
radiation therapy, biologics for cancer, intravesical therapy, or
investigational therapy within 28 days of first administration of study
treatment.
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 | CTIS2022-500630-29-00 |
| EudraCT | EUCTR2014-003626-40-NL |
| CCMO | NL55662.018.16 |