A Study of Nivolumab Plus Bempegaldesleukin (Bempeg/NKTR-214) vs Nivolumab Alone vs Standard of Care in Participants With Bladder Cancer That May Have Invaded The Muscle Wall of the Bladder and Who Cannot Get Cisplatin, A Type of Medicine Given To Treat Bladder Cancer

A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus Bempegaldesleukin (NKTR-214), Versus Nivolumab Alone Versus Standard of Care in Participants With Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04209114

Enrollment

114

Registered

2019-12-23

Start date

2020-02-05

Completion date

2023-06-07

Last updated

2024-06-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bladder Cancer, Bladder Tumor, Muscle-Invasive Bladder Cancer

Keywords

immunotherapy, NKTR-214, nivolumab, bempeg

Brief summary

The purpose of the study is to see if treatment with nivolumab plus bempegaldesleukin or nivolumab alone, before and after surgery to remove the bladder, is more effective than surgery alone in participants with high-risk urothelial cancer, including muscle-invasive bladder cancer who are not able to receive cisplatin chemotherapy.

Interventions

BIOLOGICALNivolumab

Specified dose on specified days

PROCEDURERadical cystectomy (RC)

Surgical removal of the bladder

BIOLOGICALBempegaldesleukin

Specified dose on specified days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Urothelial carcinoma (UC) of the bladder, clinical stage T2-T4aN0, M0 or T1-T4aN1, M0, diagnosed at transurethral resection of bladder tumor (TURBT) * Must be deemed eligible for Radical Cystectomy (RC) by urologist, and must agree to undergo RC. For arms A and B, participants must agree to undergo RC after completion of neoadjuvant therapy. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Cisplatin-ineligible participants will be defined by any one of the following criteria: i) Impaired renal function (glomerular filtration rate \[GFR\] ≥ 30 but \< 60 mL/min) ii) GFR should be assessed by direct measurement (ie, creatinine clearance) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula) iii) Common Terminology Criteria for Adverse Events (CTCAE) version 5, ≥ Grade 2 hearing loss (assessed per local SOC). iv) CTCAE version 5, ≥ Grade 2 peripheral neuropathy. * Documented Left Ventricular Ejection Fraction (LVEF) more than 45%

Exclusion criteria

* Clinical evidence of ≥ N2 or metastatic bladder cancer * Prior systemic therapy, radiation therapy, or surgery for bladder cancer other than TURBT or biopsies is not permitted. Prior Bacillus Calmette-Guerin (BCG) or other intravesicular treatment of non-muscle invasive bladder cancer (NMIBC) is permitted if completed at least 6 weeks prior to initiating study treatment. * Evidence of urothelial carcinoma (UC) in upper urinary tracts (ureters or renal pelvis) or history of previous MIBC * History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically significant venous or non-CVA(cerebrovascular accident)/TIA (Transient ischemic attack) arterial thromboembolic event * Known cardiovascular history, including unstable or deteriorating cardiac disease within the previous 12 months (including unstable angina or myocardial infarction, congestive heart failure or uncontrolled clinically significant arrhythmias) Other protocol-defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care	From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)	Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.
Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care	From randomization up to first EFS event (up to approximately 30 months)	Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).

Secondary

Measure	Time frame	Description
Overall Survival (OS)	From randomization to study completion, up to approximately 40 months	Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. OS was not calculated for Arm A and Arm B because the number of events did not meet the threshold due to early study termination. In lieu of OS, time to death is reported as a Post-Hoc endpoint.
The Number of Participants Experiencing Adverse Events (AEs)	from first dose to 100 days following last dose (up to approximately 20 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
The Number of Participants Experiencing Serious Adverse Events (SAEs)	from first dose to 100 days following last dose (up to approximately 20 months)	A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization.
Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care	From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)	Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.
The Number of Participants Experiencing Immune-Mediated Adverse Events (IMAEs)	from first dose to 100 days following last dose (up to approximately 20 months)	IMAEs are specific AEs that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis), and other specific events, considered as potential immune-mediated events by investigator that meet the definition summarized below: * those occurring within 100 days of the last dose, * regardless of causality, * treated with immune-modulating medication (of note, endocrine AEs such as adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating medication use, since endocrine drug reactions are often managed without immune-modulating medication). * with no clear alternate etiology based on investigator assessment, or with an immune-mediated component.
Worst Grade Clinical Laboratory Values	From first dose to 100 days following last dose (up to approximately 20 months)	Clinical laboratory values by worst CTC grade are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation	from first dose to 100 days following last dose (up to approximately 20 months)	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
Event Free Survival (EFS) - Nivolumab Compared to Standard of Care	From randomization up to first EFS event (up to approximately 30 months)	Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).

Countries

Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Israel, Italy, Mexico, Netherlands, Poland, Russia, Spain, United Kingdom, United States

Participant flow

Pre-assignment details

Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue to receive nivolumab monotherapy.

Participants by arm

Arm	Count
Arm A: Nivolumab + Bempegaldesleukin Bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by bempegaldesleukin 0.006 mg/kg once every 3 weeks plus nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.	37
Arm B: Nivolumab Nivolumab 360 mg once every 3 weeks for 3 cycles as neoadjuvant therapy, followed by Radical Cystectomy, followed by nivolumab 360 mg once every 3 weeks up to an additional 12 cycles.	37
Arm C: Standard of Care Standard of care therapy, with cystectomy alone, without neoadjuvant or adjuvant therapy.	40
Total	114

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Pre-Treatment Phase	Completed without radical cystectomy	0	0	5
Pre-Treatment Phase	Death	0	0	1
Pre-Treatment Phase	Other reasons	0	0	1
Pre-Treatment Phase	Participant withdrew consent	0	0	1
Treatment Phase	Adverse event unrelated to study drug	1	5	0
Treatment Phase	Death	4	1	0
Treatment Phase	Disease progression	6	9	0
Treatment Phase	Lost to Follow-up	1	0	0
Treatment Phase	Other reasons	5	3	0
Treatment Phase	Participant withdrew consent	1	0	0
Treatment Phase	Study drug toxicity	4	6	0

Baseline characteristics

Characteristic	Arm C: Standard of Care	Total	Arm A: Nivolumab + Bempegaldesleukin	Arm B: Nivolumab
Age, Continuous	74.5 Years STANDARD_DEVIATION 8.4	74.0 Years STANDARD_DEVIATION 8.2	73.0 Years STANDARD_DEVIATION 8.8	72.0 Years STANDARD_DEVIATION 7.5
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	6 Participants	1 Participants	2 Participants
Race (NIH/OMB) White	36 Participants	107 Participants	36 Participants	35 Participants
Sex: Female, Male Female	9 Participants	22 Participants	6 Participants	7 Participants
Sex: Female, Male Male	31 Participants	92 Participants	31 Participants	30 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	8 / 37	6 / 37	12 / 40
other Total, other adverse events	32 / 37	29 / 37	18 / 32
serious Total, serious adverse events	16 / 37	22 / 37	15 / 32

Outcome results

Primary

Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care

Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).

Time frame: From randomization up to first EFS event (up to approximately 30 months)

Population: All randomized participants in Arms A and C

Arm	Measure	Value (MEDIAN)
Arm A: Nivolumab + Bempegaldesleukin	Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care	22.11 Months
Arm C: Standard of Care	Event Free Survival (EFS) - Nivolumab + Bempegaldesleukin Compared to Standard of Care	15.18 Months

Primary

Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care

Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.

Time frame: From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)

Population: All randomized participants in Arms A and C

Arm	Measure	Value (NUMBER)
Arm A: Nivolumab + Bempegaldesleukin	Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care	10.8 Percentage of participants
Arm C: Standard of Care	Pathologic Complete Response (pCR) Rate- Nivolumab + Bempegaldesleukin Compared to Standard of Care	2.5 Percentage of participants

Secondary

Event Free Survival (EFS) - Nivolumab Compared to Standard of Care

Time frame: From randomization up to first EFS event (up to approximately 30 months)

Population: All randomized participants in Arms B and C

Arm	Measure	Value (MEDIAN)
Arm A: Nivolumab + Bempegaldesleukin	Event Free Survival (EFS) - Nivolumab Compared to Standard of Care	NA Months
Arm C: Standard of Care	Event Free Survival (EFS) - Nivolumab Compared to Standard of Care	15.18 Months

Secondary

Overall Survival (OS)

Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. OS was not calculated for Arm A and Arm B because the number of events did not meet the threshold due to early study termination. In lieu of OS, time to death is reported as a Post-Hoc endpoint.

Time frame: From randomization to study completion, up to approximately 40 months

Population: All randomized participants

Arm	Measure	Value (MEDIAN)
Arm A: Nivolumab + Bempegaldesleukin	Overall Survival (OS)	NA Months
Arm C: Standard of Care	Overall Survival (OS)	NA Months
Arm C: Standard of Care	Overall Survival (OS)	23.23 Months

Secondary

Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care

Time frame: From time of radical cystectomy up to 100 days after last treatment (up to approximately 17 months)

Population: All randomized participants in Arms B and C

Arm	Measure	Value (NUMBER)
Arm A: Nivolumab + Bempegaldesleukin	Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care	10.8 Percentage of participants
Arm C: Standard of Care	Pathologic Complete Response (pCR) Rate - Nivolumab Compared to Standard of Care	2.5 Percentage of participants

Secondary

The Number of Participants Experiencing Adverse Events (AEs)

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.

Time frame: from first dose to 100 days following last dose (up to approximately 20 months)