Primary Objectives• To compare the pathologic complete response (pCR) rate of neoadjuvant nivolumab + NKTR-214 to Standard of Care (SOC, no neoadjuvant therapy) in all randomized participants• To compare the event-free survival (EFS) of neoadjuvant…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• pCR rate, defined by the proportion of randomized participants with absence
of any cancer (T0, N0,M0) in pathology specimens after RC, based on blinded
independent pathology review
• EFS, defined as the time from randomization to any of the following events:
progression of disease that precludes surgery, local or distant recurrence
based on BICR assessments, or death due to any cause
Secondary outcome
• pCR rate, defined by the proportion of randomized participants with absence
of any cancer (T0, N0,M0) in pathology specimens after RC, based on blinded
independent pathology review
• EFS, defined as the time from randomization to any of the following events:
progression of disease that precludes surgery, local or distant recurrence
based on BICR assessments, or death due to any cause
• OS, defined as the time between the date of randomization and the date of
death from any cause. OS will be censored on the last date a subject was known
to be alive.
• Worst grade AEs, SAEs, AEs leading to discontinuation, immune-mediation AEs
and worst grade clinical laboratory values
Background summary
Patients with muscle-invasive bladder cancer (MIBC), defined as stage T2-T4a,
N0, and M0, are at a high risk for the developing metastatic disease, even
after receiving SOC treatment RC. For patients with MIBC who are eligible to
receive cisplatin-based chemotherapy, Level 1 evidence demonstrates a
significant increase in overall survival (OS) with the use of neoadjuvant
chemotherapy. The SWOG 8710 Phase 3 study, which compared neoadjuvant MVAC
(methotrexate, vinblastine, doxorubicin, cisplatin) plus RC to RC alone, showed
a 66% increased risk of death from bladder cancer and a 33% risk of death from
all causes in patients who received RC alone compared to combination treatment.
Cisplatin-ineligible patients account for 40% to 50% of the total population
with MIBC. Patients with MIBC who are ineligible for cisplatin-based
chemotherapy due to poor renal function (usually defined as a creatinine
clearance of < 60 mL/minute), advanced age, hearing loss, peripheral
neuropathy, or poor performance status represent a population with a high unmet
medical need because there is currently no recommended neoadjuvant therapy (or
adjuvant therapy) for this group. SOC for these patients is to proceed directly
to RC, which is associated with a 50% recurrence rate at 5 years, with most of
these patients dying from metastatic urothelial cancer within 1 year.
This Phase 3 study in the neoadjuvant and adjuvant treatment of MIBC for
patients ineligible for cisplatin will allow for direct comparison of nivolumab
plus NKTR-214 versus SOC treatment with RC alone. The study is designed with an
analysis of the rate of pCR and will continue follow-up for an analysis of EFS.
Study objective
Primary Objectives
• To compare the pathologic complete response (pCR) rate of neoadjuvant
nivolumab + NKTR-214 to Standard of Care (SOC, no neoadjuvant therapy) in all
randomized participants
• To compare the event-free survival (EFS) of neoadjuvant nivolumab + NKTR-214
followed by adjuvant nivolumab + NKTR-214 after radical cystectomy (RC) versus
SOC (no neoadjuvant or adjuvant therapy)
Secondary Objectives
• To compare the pCR rate of neoadjuvant nivolumab monotherapy to SOC (no
neoadjuvant therapy) at the time of surgery
• To compare the EFS of neoadjuvant nivolumab followed by adjuvant nivolumab
versus SOC
• To compare the overall survival (OS) of each experimental arm versus SOC
• To assess safety and tolerability for each treatment arm
Study design
This study is an open-label, phase 3 trial aiming to demonstrate that treatment
with nivolumab combined with NKTR-214 will increase the rate of pathologic
complete response and prolong event-free survival (ESF) in cisplatin ineligible
participants with MIBC who undergo RC.
Approximately 540 patients will be treated globally.
Participants will be randomized (1:1:1) to one of the following 3 treatment
arms:
• Treatment Arm A: NKTR-214 + nivolumab every 3 weeks for a maximum of 3 cycles
as neoadjuvant therapy, followed by RC, followed by NKTR-214 + nivolumab every
3 weeks up to an additional 12 cycles (approximately 9 months of adjuvant
therapy).
• Treatment Arm B: Nivolumab every 3 weeeks for a maximum of 3 cycles as
neoadjuvant therapy, followed by RC, followed by nivolumab every 3 weeks up to
an additional 12 cycles (approximately 9 months of adjuvant therapy).
• Treatment Arm C: SOC (cystectomy alone, without neoadjuvant or adjuvant
therapy).
After treatment, all subjects will enter the follow-up phase of the study.
Subjects will have 2 visits within the first 100 days after stopping treatment.
The remaining follow-up visits can be conducted over the phone and will occur
every 3 months.
Intervention
Participants will be randomized (1:1:1) to one of the following 3 treatment
arms:
• Treatment Arm A: NKTR-214 0.006 mg/kg Q3W + nivolumab 360 mg Q3W x 3 cycles
as neoadjuvant therapy, followed by RC, followed by NKTR-214 0.006 mg/kg Q3W +
nivolumab 360 mg Q3W up to an additional 12 cycles (approximately 9 months of
adjuvant therapy).
• Treatment Arm B: Nivolumab 360 mg Q3W x 3 cycles as neoadjuvant therapy,
followed by RC, followed nivolumab 360 mg Q3W up to an additional 12 cycles
(approximately 9 months of adjuvant therapy).
• Treatment Arm C: SOC (Cystectomy alone, without neoadjuvant or adjuvant
therapy).
Both nivolumab and NKTR-214 are provided by the sponsor.
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,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events & serious adverse events.
Patients will be asked to complete questionnaire*s (FACT-G, FACT-BI-Cys &
EQ-5Q-3L) about their quality of life. Blood will also be collected at certain
visits for research purposes (PK, immunogenicity and biomarker studies) as well
as (optional) stool samples for microbiome analysis. If there is no archival
tumour tissue available or the sample was taken too long ago (>=3 months),
patients will be required to have a biopsy in order to participate. Radical
cystectomy will be performed on patients post completion of neo-adjuvant
therapy. Patients who do not undergo radical cystectomy, will be surveyed for
disease recurrence/progression by cystoscopy, every 3 months for the next two
years and then every 6 months for 3 additional years, then once per year. For
these patients, maximal TURBT of all visible tumor should be performed on the
first on-treatment cystoscopy. Patients will undergo radiographic assessment of
their tumors by CT or MRI at screening. Imaging will continue for patients for
a maximum of 5 years or until: investigator assessed disease progression that
precludes surgery, or until Blinded Independent Central Review confirms
progression or recurrence, at intervals of every 12 weeks for up to 2 years
(from the date of first neoadjuvant dose), then every 24 weeks up to a maximum
of 5 years. The frequency of visits and number of procedures carried out during
this trial would be typically 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. To assure an ongoing favourable risk/benefit assessment for
patients enrolled onto the study, an Independent Data Monitoring Committee
(DMC) will be established to provide oversight of safety and efficacy
considerations. Additionally, the DMC will provide advice to the sponsor
regarding actions the committee deems necessary for the continuing protection
of patients enrolled in the study.
BMS will conduct rigorous safety monitoring to ensure patients safety by
regularly & systematically reviewing safety data; the reported safety events
will be closely followed-up; sites and study investigators will receive
training on the implementation of the NKTR-214 and nivolumab toxicity
management strategies. New immune system targeted therapy (immunotherapies)
such as nivolumab could potentially provide clinical benefit and improvements
in the outcomes for patients with this disease. 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.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
• Participants with MIBC, clinical stage T2-T4a, N0 (< 10 mm on CT or MRI), M0,
diagnosed at TURBT within 12 weeks of randomization
• Participant must be deemed eligible for RC by urologist. Arms A and B must
agree to undergo RC after completion of neoadjuvant therapy.
• PD-L1 >= 1% or PDL1 < 1% as determined by a central laboratory during the
screening period and the results must be submitted to IRT prior to
randomization. Indeterminate participants are allowed in the study.
Formalin-fixed, paraffin-embedded (FFPE) tissue block or 20 unstained tumor
tissue sections with an associated pathology report, submitted for biomarker
evaluation prior to randomization. Tumor tissue sample from a biopsy may be
fresh or a recent sample (< 12 weeks old), and should be from the TURBT or
biopsy that made the diagnosis of MIBC. No systemic therapy (e.g., adjuvant or
neoadjuvant chemotherapy) given after the sample was obtained.
• Documented left ventricular ejection fraction (LVEF) > 45% within 60 days
prior to randomization using standard echocardiogram or multigated acquisition
(MUGA) scan test
• ECOG performance status 0 or 1
• Cisplatin-ineligible participants:
- Impaired renal function (GFR >= 30 but < 60 mL/min); GFR should be assessed
by direct measurement or, if not available, by calculation from serum/plasma
creatinine
- CTCAE version 5, >= Grade 2 hearing loss
- CTCAE version 5, >= Grade 2 peripheral neuropathy
Exclusion criteria
• Clinical evidence of pathologic LN (>= 10 mm in short axis) or metastatic
bladder cancer
• Prior systemic therapy, radiation therapy, or surgery for bladder cancer
other than TURBT or biopsies is not permitted. Prior BCG or other intravesical
treatment of NMIBC is permitted if completed at least 6 weeks prior to
initiating study treatment
• Evidence of UC in upper urinary tracts (ureters or renal pelvis) or history
of previous MIBC.
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 | EUCTR2018-002676-40-NL |
| CCMO | NL68356.056.19 |
| Other | U1111-1216-7529 |