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Urothelial CarcinomaPhase 1NABUCCONCT03387761

Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy

A Phase 1 study testing Ipilimumab and Nivolumab in people with Urothelial Carcinoma, run by The Netherlands Cancer Institute at 3 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

In cohort 1 of this study, we used an attenuated schedule of neoadjuvant ipilimumab and nivolumab. In the multicenter extension (cohort 2), 30 patients were randomized between two neoadjuvant treatment schemes, both based upon an attenuated schedule of neoadjuvant ipilimumab and nivolumab.Both cohorts are completed. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Urothelial Carcinoma
What is being tested?
Ipilimumab and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
3 sitesNetherlands
Study dates
15 Jan 2018to 7 Jan 2025
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Willing and able to provide informed consent
  • Age ≥ 18 years
  • High-risk resectable urothelial cancer (upper urinary tract allowed) defined as stage III UC:
  • cT3-4aN0M0 OR cT1-4aN1-3M0 4. Refusal of neoadjuvant/induction cisplatin-based chemotherapy or patients in whom neoadjuvant cisplatin based therapy is not appropriate.
  • 5. World Health Organization (WHO) performance Status 0 or 1. 6. Urothelial cancer is the dominant histology (>70%). 7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available (or any other FFPE tumor specimens for upper tract tumors).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, AST ≤ 2.5 x ULN, ALT ≤2.5 x ULN, Bilirubin ≤1.5 X ULN 9. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
  • 10. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 180 days after the last dose of immunotherapy Adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms, oral contraceptives, intra-uterine device.

Who cannot join

  • 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.
  • Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
  • Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
  • Known history of Human Immunodeficiency Virus, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA), active tuberculosis, or other active infection requiring therapy at the time of inclusion.
  • Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
  • 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 (eg, CT scan premedication) will be allowed.
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  • Use of other investigational drugs before study drug administration
  • 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.
  • Pregnant and lactating female patients.
  • 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.
  • Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
  • 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, or unstable angina.
  • Previous intravenous chemotherapy for bladder cancer. Prior chemoradiation is allowed.
  • Patients in whom use of a colon segment for urinary diversion is planned

Trial locations and contacts

3 sites in 1 country.

Netherlands3 sites

  • Antoni van Leeuwenhoek ziekenhuis

    Amsterdam, North Holland, 1066CX

  • Radboud UMC

    Nijmegen

  • UMC Utrecht

    Utrecht

Other trials in Netherlands

About this study

Official title: Phase 1B Study to Assess Safety and Efficacy of Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)

In cohort 1 of this study, we used an attenuated schedule of neoadjuvant ipilimumab and nivolumab. In the multicenter extension (cohort 2), 30 patients were randomized between two neoadjuvant treatment schemes, both based upon an attenuated schedule of neoadjuvant ipilimumab and nivolumab.Both cohorts are completed.

Read the detailed description

This is an open-label phase Ib trial to evaluate three different schedules of preoperative ipilimumab and nivolumab. Urothelial cancer patients will be included that are diagnosed with either:

  • cT3-4aN0M0 OR
  • T1-4aN1-3M0

Cohort 1 (n=24):

  • Day 1: Ipilimumab 3 mg/kg
  • Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

Patients in cohort 2 (n=30) were randomized between cohort 2a and 2b

Cohort 2a (n=15):

  • Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

Cohort 2b (n=15):

  • Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg
  • Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

The primary endpoint for cohort 1 in this trial was safety. We determined the number of patients that had surgical resection <12 weeks from first infusion, as this is an endpoint that is clinically meaningful for this population. After surgery, patients attended study visits at day 8 and day 29. Their final study visit for physical examination and laboratory testing is at day 57 (+/- 7 days), which is scheduled to anticipate late-onset adverse events (particularly endocrine). After this final visit, patients were followed according to standard clinical guidelines. Tumor biopsies/material preservation were required at baseline and during surgery.

In cohort 2, we randomized patients between 2 arms. Here, the main secondary outcomes were:

  • To compare the efficacy of pre-operative ipilimumab + nivolumab in cohort 1 (sequenced ipilimumab/nivolumab), versus cohort 2a (ipi 3 mg/kg and nivo 1 mg/kg) and cohort 2b (ipi 1 mg/kg and nivo 3 mg/kg). Efficacy was defined as the pCR rate at resection.
  • Provide an estimate of ≥grade 3 immune-related toxicity in the ipi3/nivo1 and ipi1/nivo3 cohorts as opposed to the initial cohort (Cohort 1)

An important additional secondary endpoint is translational. The main testable hypothesis is that a significant percentage of nonresponse can be explained by immune-inhibitory processes. Absence of immune infiltrates, presence of significant numbers of regulatory T-cells and presence of significant numbers of myeloid-derived suppressor cells will be compared between responders and nonresponders. The efficacy will be defined as the percentage of pathological complete response (pCR) at cystectomy (secondary endpoint).

Being tested
Ipilimumab, Nivolumab
Keywords
Urothelial cancer, Bladder cancer, Cancer, Resectable, Operable, immunotherapy, Ipilimumab, Nivolumab, Neo-Adjuvant
Medical subject headings
Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IpilimumabDrug

    Also called BMS-734016, Yervoy

    For Cohort 1:

    • Day 1: Ipilimumab 3 mg/kg
    • Days 22: Ipilimumab 3 mg/kg

    For Cohort 2a:

    • Day 1: Ipilimumab 3 mg/kg
    • Days 22: Ipilimumab 3 mg/kg

    For Cohort 2b:

    • Day 1: Ipilimumab 1 mg/kg
    • Days 22: Ipilimumab 1 mg/kg

  • NivolumabDrug

    Also called BMS-936558, Opdivo

    For Cohort 1:

    • Day 22: Nivolumab 1 mg/kg
    • Day 43: Nivolumab 3 mg/kg

    For Cohort 2a:

    • Days 1 and 22: Nivolumab 1 mg/kg
    • Day 43: Nivolumab 3 mg/kg

    For Cohort 2b:

    • Days 1, 22 and 43: Nivolumab 3 mg/kg
Study groups in NCT03387761
Study groupRoleWhat they receive
Cohort 1: Ipi + NivoExperimental* Day 1: Ipilimumab 3 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v.
Receives: Drug: Ipilimumab; Drug: Nivolumab
Cohort 2a: high-Ipi + low-NivoExperimental* Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
Receives: Drug: Ipilimumab; Drug: Nivolumab
Cohort 2b: low-Ipi + high-NivoExperimental* Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
Receives: Drug: Ipilimumab; Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of patients that had surgical resection <12 weeks after study start (Cohort 1)

    Percentage of patients that underwent surgery within 12 weeks after study start were assessed

    Measured: At 12 weeks

Secondary outcomes (8)

  1. Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) after cystectomy (Cohort 1, followed by Cohort 2a versus 2b)

    pCR rate after cystectomy according to pathological response criteria

    Measured: At 12 weeks

  2. Differences in immune infiltrates in responders vs nonresponders

    Resistance mechanisms are explored by comparing immune (cell) infiltrates in responders and nonresponders in pre- and post treatment tissue [Multiplex immunohistochemistry, RNA seq]

    Measured: At 12 weeks

  3. T-cell (dys)functionality as measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy tissue

    This component is done in a minority of patients on T cell lysates if a re-TUR (transurethral resection) pre-treatment was done.

    Measured: At 12 weeks

  4. Explore whether radiomics-based predictive models can be established for immunotherapy responders vs non-responders (Cohort 1)

    CT and MRI images will be assessed in this manner to optimize recognition of an immunotherapy response.

    Measured: At 12 weeks

  5. Provide an estimate of ≥grade 3 immune-related toxicity in cohorts 2a versus 2b

    Immune-related toxicity were compared between cohhort 1 and cohort 2 and between cohorts 2a and 2b

    Measured: At 12 weeks

  6. Monitor peri-surgical complications.

    peri-operative complications and morbidity were graded according to the Clavien-Dindo classification.

    Measured: Until 90 days after surgery.

  7. ctDNA in plasma during follow-up

    Assessment of ctDNA in plasma during follow-up and at recurrence

    Measured: During follow-up and with disease recurrence

  8. As part of regular follow-up after radical surgery, follow-up CT scans were made after 1 and 2 years.

    As part of regular follow-up after radical surgery, follow-up CT scans were made after 1 and 2 years. Additional scans were performed according to local standards.

    Measured: Until 2 years after surgery (not part of primary study assessment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jan 2018
  2. Study start15 Jan 2018
  3. Primary completion19 Jul 2021
  4. Study completion7 Jan 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Multicenter, open-label phase 1b clinical trial
Masking
None (open label)
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03387761
Sponsor's protocol ID
N17NAB
Other IDs
CA209-9Y4
Acronym
NABUCCO
Status last verified
Mar 2025
First submitted
24 Nov 2017
Last updated
5 Mar 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Stockem CF, van Dorp J, van Dijk N, Vis DJ, Harkes R, van den Broek B, Alkemade M, Broeks A, Hendricksen K, Boellaard TN, de Feijter JM, van Montfoort ML, Daletzakis A, van der Heijden AG, Meijer RP, Mehra N, Wessels LFA, van Rhijn BWG, Suelmann BBM, van der Heijden MS. Final clinical analysis of pre-operative ipilimumab and nivolumab in locally advanced urothelial cancer and exploration of tumor-draining lymph node composition: The NABUCCO trial. Eur J Cancer. 2025 Oct 16;229:115731. doi: 10.1016/j.ejca.2025.115731. Epub 2025 Aug 21.

    PubMed 40934711

  • van Dorp J, Pipinikas C, Suelmann BBM, Mehra N, van Dijk N, Marsico G, van Montfoort ML, Hackinger S, Braaf LM, Amarante T, van Steenis C, McLay K, Daletzakis A, van den Broek D, van de Kamp MW, Hendricksen K, de Feijter JM, Boellaard TN, Meijer RP, van der Heijden AG, Rosenfeld N, van Rhijn BWG, Jones G, van der Heijden MS. High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial. Nat Med. 2023 Mar;29(3):588-592. doi: 10.1038/s41591-022-02199-y. Epub 2023 Feb 2.

    PubMed 36732628

  • van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, van Montfoort ML, van Rooijen C, Peters D, Broeks A, van der Poel HG, Bruining A, Lubeck Y, Sikorska K, Boellaard TN, Kvistborg P, Vis DJ, Hooijberg E, Schumacher TN, van den Broek M, Wessels LFA, Blank CU, van Rhijn BW, van der Heijden MS. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020 Dec;26(12):1839-1844. doi: 10.1038/s41591-020-1085-z. Epub 2020 Oct 12.

    PubMed 33046870

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ipilimumab and Nivolumab in people with Urothelial Carcinoma, run by The Netherlands Cancer Institute at 3 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients that had surgical resection <12 weeks after study start (Cohort 1) (time frame: At 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03387761, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2025.

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